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History History of present illness of olfactory receptor neurons with be needed as well, particularly improves their enjoyment of eating. Abstract Kallmann syndrome KS can be characterized as genetic disorder marked by hypogonadotropic hypogonadism and anosmia. Some studies have found greater numbers and activity of NK cells from male rodents compared with females 4 , Another study of healthy geriatric individuals found that while there was an initial surplus of NK cells in men less than 70 years of age, there was a steep increase and superiority in NK cell function in women over 70 years 17 , This post-menopausal finding seems to defy other studies that found a rise in NK cells during the periovulatory phase when estrogen and progesterone are increased 4 , It is possible, however, that even if estrogen derivatives increase the number of NK cells, the cytotoxic capabilities of these cells may be reduced.

In contrast, Th2 cells produce cytokines that are more anti-inflammatory and redirect focus to humoral immunity mechanisms. The homeostasis between Th1 and Th2 cells is vital for the obliteration of infectious microbes without causing pathological states in the host. The SARS coronavirus of is notable in that it exclusively produced an activation of Th1 cells and cytokines in the host.

These protein levels were elevated for at least 2 weeks after onset and were sufficient for full recovery of the host. Across several studies, induction of anti-inflammatory Th2 pathways was not necessary for host survival 30 — The novel coronavirus SARS-CoV-2, however, seems to work differently when compared to its older relative, as sufficient induction of anti-inflammatory Th2 response is necessary.

Levels of these cytokines were much lower in non-ICU patients and the control group 32 , indicating that pathogenic Th1 cells correlate with the hyper-inflammatory response in SARS-CoV-2 pathogenesis. Physiologic changes within the immune system during pregnancy typically involve an attenuation of the Th1 response and a shift toward Th2 anti-inflammatory pathways 31 , This is in the interest of protecting the developing fetus from an overactive cell-mediated immune response, while simultaneously developing antibodies for passive transfer of immunity through the placenta and breast milk.

Although there may be numerous variables at play, it seems that host survival in COVID is tied to substitution of the proinflammatory Th1 for the anti-inflammatory Th2 that is dominant in gravid hosts. In coronavirus infections, IL encourages the assembly of downstream proinflammatory cytokines that result in activation of neutrophil chemokines and secretory elements that damage lung parenchyma An investigation of polymorphisms for IL genes in SARS patients showed that individuals predisposed to lower levels of IL activation had significantly increased day survival when compared with patients prone to increased IL production Th17 lymphocytes also contribute to ARDS pathogenesis by activation of IL, which seems involved in the production of mucin and fibrin-rich secretions in patients with pulmonary edema 36 , While the role of gender in relation to Th17 function in coronavirus infections has yet to be studied, there is some literature on how this cell type affects AD.

In AD that predominantly affect males, there has been significant literature on Th17 cells playing a paramount role in disease progression 37 — For example, although multiple sclerosis MS affects 2—3 times more women than men, men tend to experience more rapid and aggressive disease progression Similarly, in systemic lupus erythematosus SLE which afflicts women 9—10 times more often than men, men tend to experience more severe complications especially nephritis leading to renal failure.

This finding suggested that male sex is a crucial and inherent element of disease-induced severity related to Th17 cells. Whether this finding is applicable to host attack in the context of SARS remains to be determined. The optimal balance of these activities is different for every pathogen, but, in the context of mouse hepatitis virus MHV coronavirus, Tregs are necessary for mild disease outcomes, as their depletion results in increased mortality 40 , While studies of Treg influences and functions have been performed on several types of respiratory viruses, there is little information on their roles against human coronaviruses.

The role and activity of Treg lymphocytes, therefore, cannot yet be verified in the context of COVID, but these cells may offer a benefit by reducing excessive damage to lung parenchyma. The transcription factor Foxp3 serves not only as a marker for Treg cells, but it is also necessary for their development, maintenance, and suppressive functions 42 , Foxp3 is encoded on the X chromosome and can escape X inactivation, giving XX females higher activity of Foxp3 and Treg cells 33 , This may give women an immunosuppressive advantage in the context of coronaviruses.

Scarcity of Treg cells from loss-of-function alterations in Foxp3 lead to severe and even lethal inflammation in human and rodent models of coronavirus infection Across several studies, there are a significant portion of COVID patients who present with lymphopenia and markers of T cell exhaustion. It was found that as patients progressed from prodromal to active symptoms, their levels of PD1 and Tim3 would directly increase.

In the same vein, patients in the ICU had much higher expression of these markers compared to non-ICU and control populations 44 , Consistent with previous work, these markers were significantly elevated in critically ill patients compared with those who were only mildly symptomatic with COVID Causes and effects of lymphopenia have not been thoroughly studied in SARS, and much less can be said for differences in sex. After an initial encounter with a pathogen, antigen-specific naive CD4 and CD8 T cells clonally expand to become effector T cells, which mount a cellular and humoral response against the offending pathogen.

After pathogen clearance, most effectors die by apoptosis, while some survive and persist to become long-lived memory T cells, and it is these cells that offer the host protection from subsequent encounters with the pathogen. Memory cells also form the basis for vaccinations which elicit a similar immune response albeit at a significantly reduced magnitude without causing disease.

Memory T cells are heterogeneous in phenotype, function and localization and include central memory Tcm , effector memory Tem , tissue resident memory Trm , terminally differentiated memory Temra , and other cells These antigen-specific cells are the basis of vaccine development, as they are skilled in triggering a targeted immune response upon re-exposure to an antigen. As SARS-CoV-2 is a novel infection, development and viability of memory T cells in men and women is truly unknown, especially in the face of viral mutation.

As SARS-CoV-2 is a novel infection, development and maintenance of memory T cells in men and women is truly unknown, especially in the face of viral mutation. Antibody secretion is the primary function of B lymphocytes. As expected, IgG antibody levels were stable while IgM antibodies reached low levels within 5 weeks and became undetectable at 7 weeks This may have to do with the upregulation of IL-4, IL, and other cytokines promoting antibody class-switching at an ultra-rapid rate These interleukins are part of the Th2 pathway which is naturally enhanced in women, suggesting that there may be a physiological sex difference in antibody switching, although no known studies have been done in this specific area 32 Another study investigated IgG levels between male and female COVID patients, stratifying patients by disease severity into mild, moderate, and severe status and into early, active, and recovery phases.

While there was no significant difference in serum IgG levels across gender in mild and recovering patients, IgG levels in women were significantly elevated in the early disease phase and in severe cases This situational increase in antibody titers cannot yet be determined as helpful or harmful in SARS, but it is worth noting for future investigation. B-cell production of cytokines make these lymphocytes powerful regulators of adaptive immunity, but in many cases turn maladaptive, such as in SARS.

A series of seven case studies was recently published on B-cell immunocompromised COVID patients and sheds light on the excessive lymphocyte immune response. Disease presentation of patients with common variable immune deficiency CVID hypogammaglobulinemia were compared to patients with agammaglobulinemia AGG.

Surprisingly, the AGG cases proved to be mild, and the patients had normal lung CT scans with no consolidation. The patients were treated in the hospital for a maximum of 3 days and went home without requiring assisted ventilation. They were in the hospital for at least two weeks and needed antiretroviral therapy ART , IL antagonists, and some required mechanical ventilation.

According to the study, the difference in patient outcomes was likely due to the lack of non-Ig B cell cytokine functions, meaning that patients with AGG avoided a host-harming cytokine storm. This cytokine activation is linked to stimulation of TLR in T-cell independent activation This process authorizes B cells to respond to activation from coronavirus-TLR7 binding by immediate expansion and differentiation without much T cell interaction.

These mature and activated B cells are capable of producing IgM as well as proinflammatory cytokines, namely IL Contrary to other immune cells discussed above , it seems that B-cell-derived cytokines may be more harmful to a female host. Women mount a stronger immune response against viral infections than men Women possess both maternal and paternal X chromosomes, which necessitates the silencing of one copy of genes in order to ensure an appropriate gene dosage.

The silencing of one copy, or X chromosome inactivation XCI , leads to functional mosaicism in women with regards to X-linked genes X chromosome inactivation is cell-specific and variable among individuals, which causes some cells to express the maternal chromosomal copy and others to express the paternal copy. In turn, this leads to a diversity of possible immune responses in females, which provides women with a wider variety of tools with which to fight pathogens Skewed inactivation patterns may additionally offer a protective effect by silencing immunodeficiency-causing mutations Furthermore, X-chromosome skewing may preferentially express beneficial alleles, leading to a larger proportion of cells producing functionally advantageous gene products X chromosome inactivation is particularly relevant to discussion of the SARS-CoV-2 immune response, as the X chromosome encodes for several genes involved in both adaptive and innate immunity, including those involved in the TLR pathway Cellular mosaicism suggests that women may be better equipped to respond to immune challenges, particularly viral infections such as SARS-CoV Evidence shows that XCI escape commonly occurs in female lymphocytes, which display atypical heterochromatic modification and tend to reactivate the inactivated X chromosome Xi The XCI escape of genes involved in the immune system may further contribute to an immunologic advantage in women.

The gene for TLR7 is located at Xp When stimulated by TLR7, biallelic B cells were 2. Increased class switching suggests that women and KS males may have enhanced humoral immune response due to TLR7 overexpression. Estrogen levels likely contribute to the sex-based difference in TLR7 signaling, as immune cells from both men and women have been shown to increase TLR7 expression post-exposure to estradiol treatment 60 , As a result, inclusion of genotypically diverse individuals may lend additional insights into the impact of XCI escape on TLR7 gene dosing.

As a result, XCI escape may be correlated with increased TLR7 signaling and more vigorous immune response to viral infections. CXorf21 is located at gene locus Xp While its exact function is presently unknown, its overexpression in female APC suggests that CXorf21 may cooperate with TLR7 to contribute to the heightened antiviral response in women The gene locus for CD40L has been identified as Xq CD40L functions in several aspects of the adaptive immune response, including T-cell differentiation, immunoglobulin class switching, and formation of long-lived plasma cells and memory B cells A comparison of antigen presenting cells APCs from TS women, KS men, and individuals with typical karyotype found that cells from typical women expressed significantly more CD40L than those from typical men or TS women Klinefelter Syndrome men yielded similar results to women possessing an XX karyotype, suggesting that XCI escape may confer an advantage against viral infections by increasing CD40L expression.

Increased CD40L in individuals with an additional chromosome may cause greater T- and B-cell activation, leading to better ability to fight off viral infection. Mannose-binding lectin was found to be depleted in patients with SARS-CoV, suggesting that the complement system may aid in the response to coronavirus infection C4, which is located at the MHC, is of particular interest because of observed differences between sexes C4 protein is more abundant in the cerebrospinal fluid and plasma of men compared to women, with a greater difference observed in men and women of childbearing age 20—50 years.

Moreover, mutation in the C4 gene affects disease risk differently in men and women. Moreover, the sex-based difference in disease incidence mirrors that of C4 protein levels and is most noticeable between men and women aged 20— As a result, the discrepancy in disease rates may be attributed to variable effects of C4 between men and women. Human leukocyte antigen enables differentiation between host cells and pathogens through antigen presentation to the T-cell receptor TCR.

As MHC binding is required for effective T-cell activity, this finding is consistent with the observation that men are biased toward infections and non-reproductive system cancers hypoactive T-cell response while women are biased toward autoimmune disorders hyperactive T-cell response. For instance, incontinentia pigmenti, caused by mutations in NEMO, causes lethality in men but has variable presentation in women.

Skewed X-inactivation favoring the wildtype allele has been observed in heterozygous women, which supports the notion that X inactivation may confer a protective advantage against immunodeficiency disorders Moreover, men with KS have been observed to escape lethality from incontinentia pigmenti FoxP3 has been mapped to locus Xp Because FoxP3 does not undergo skewed X inactivation, heterozygous women express both mutant and wildtype FoxP3 alleles equally However, women heterozygous for mutant FoxP3 exhibit normal lymphocyte levels and normal immune response to infection.

The participation of FoxP3 in positive feedback loops, in which FoxP3 protein further stimulates transcription of the FoxP3 gene, indicates that one functional copy of the gene may be sufficient to maintain appropriate levels of FoxP3 As FoxP3 is critical to Treg-mediated immunosuppression, the protective effect of mosaicism implies an immunologic advantage for women at a population level As a result, the ability to curb excessive activity by cytotoxic neutrophils, macrophages, and other immune cells may decrease risk of fatality from SARS-CoV and other coronaviruses Although Tregs may offer benefit by reducing excessive tissue damage, they may also dampen the immune system and limit ability to clear an infection, indicating the need to strike a balance between the two.

While Tregs may be less important in acute viral infections requiring an aggressive immune response, the disease characteristics for SARS-CoV-2 suggest that Tregs may play a crucial role in the antiviral response. Cellular mosaicism and the resulting improvement in genetic diversity may allow women to strike this balance more easily. Given that women have two copies of the X chromosome, and that some of these genes may escape X-inactivation, this may help to explain the sex bias in immune responses.

Additionally, it has been found that miRNA that are evolutionarily conserved are more often implicated in disease states 85 , and male-specific miRNA evolve more quickly than female miRNA 84 and therefore are less conserved. Following the binding, the miRNA can either inhibit translation and decrease viral infectivity or it can stabilize the RNA and effectively increase translation.

Together, these contribute to viral evasion of the immune response. Sex hormones are an important biological factor contributing to the gender-bias in the immune response, and can influence outcomes of disease severity in infections and autoimmunity 4 , 88 — In general, estrogens are considered immuno-stimulatory and activate both the innate and adaptive immune responses and therefore women are able to clear pathogens more efficiently than men, whereas testosterone is immuno-suppressive, which may underlie the higher susceptibility and severity of infectious diseases in men 4.

On the other hand, the stronger immune response in women is thought to underlie the disproportionately high prevalence of AD in women over men. Sex hormones control both cellular and humoral components of the immune response and thus determine the sex-bias in susceptibility, manifestations and clinical outcomes in infections, AD and malignancies 4 , Sex hormones bind these receptors and trigger intracellular signaling cascades to regulate gene and protein expression to influence development, maturation, activation, and function of innate and adaptive immune cells during homoestasis and the immune response to infections.

Better understanding of the factors that control the immune response in a sex-specific manner is therefore crucial to not only understanding disease pathogenesis but also guiding treatment and prevention strategies and a first step toward personalized medicine. The sex-biased factors that impact immunity have developmental origins beginning in utero , infancy and childhood For example, placental hormones help shape fetal and neonatal immunity, and some of these influences are retained through adulthood.

Estrogen and progesterone are important in alveolarization and surfactant production respectively. For some infections and AD, these differences in susceptibility and severity are retained through adulthood but may change or even reverse for some allergy-related conditions and AD. Studies on the role of sex hormones in immune cells range from ex vivo cultures of human or mouse cells, or in vivo supplementation in mice after gonadectomy, including those assessing mice with genetic deletions of sex hormone receptors.

Given the wide variations in human versus rodents in vitro versus in vivo systems, epidemiological studies have shown that there is not a universal paradigm regarding the role of gender or sex hormones on the immune response to respiratory viruses. It is hypothesized that the disease outcomes are ultimately a combination of the magnitude of the immune response and degree of host tissue damage 92 , There is a male bias when a weaker immune response contributes to damage, while a female bias may occur due to a stronger immune response that causes damage.

Estrogen-ER signaling regulates innate myeloid cells including pDCs, monocytes, neutrophils, and lymphoid cells, including innate lymphoid cells ILC Estrogens contribute to delayed neutrophil apoptosis and can modulate chemotaxis and NO production in vitro. The lung-resident alveolar macrophages are important in respiratory infections and produce type I IFN for viral clearance.

These findings imply that wherein estrogen and ERa enhance while AR may dampen the type 2 responses important for lung tissue repair post-viral infections. While these cells predominantly express AR, there is tissue specific regulation by sex hormones and estrogen-ER signaling promoted uterine over lung ILC2. Elevated numbers in IAV infections may provide superior tissue repair, however their plasticity to convert to ILC-1 like cells and IFN-g production may make them more pathogenic and contribute to immunopathology In general, estrogens are immune-stimulatory and are known to be involved in T-cell development, activation, differentiation and function 4.

Estrogen-ER signaling was shown to be necessary for normal thymic size and development, and furthermore estrogen is known to promote extrathymic T-cell differentiation in the liver. Its role in T-cell homeostasis with respect to cell survival and proliferation is complex and varies depending on cell type, context, and concentration, where physiologic doses of estradiol suppress apoptosis whereas pharmacologic doses suppress proliferation in cancer cells. Estrogen controls cell metabolism and genes involved in metabolic activity important to stimulate T-cell differentiation and stimulate mitochondrial function.

Estrogen is known to suppress IL-2 cytokine production in human T cells 94 and rat splenocytes. Accordingly, lower IL-2 levels are observed during the luteal phase of the menstrual cycle in healthy young women and thought to contribute to the observed increase in pre-menstrual infections. CD4 T follicular helper Tfh cells are crucial for providing cognate help to B cells and promote class switching and somatic hypermutation to produce antibodies.

Estrogen was shown to promote the expression of Calcineurin and CD40L in human T cells 95 , molecules important for help to B cells in the antibody response. T cells traffic within the body to peripheral tissue sites of infection and migrate across chemokine gradients via chemokine receptors expressed on their surface.

Estrogen promotes both chemokines as well as chemokine receptor expression as evidenced by ex vivo and in vivo studies in mice 4. Estrogens also enhance CD8 T-cell activity and suppress Th17 immune responses. The role of Tregs in response to viral infections is complex. Estrogen increases FoxP3 levels and Tregs in vitro and correlations have been observed in vivo.

In women with recurrent spontaneous abortions RSA , lower Treg levels were found in both follicular and luteal phases and in postmenopausal women. The suppressive capacity of these Tregs was also lower in case of RSA. Estrogen promotes B-cell homeostasis, activation, maturation, and differentiation and enhances immunoglobulin production 4. These properties make women and female mice able to mount greater magnitudes of neutralizing antibody responses to infections and thus contribute to protection against respiratory viral infections including the SARS-CoV infections.

Estrogen administration led to increased marginal zone B cells in the spleen and in transgenic mice led to elevated anti-dsDNA antibodies. Estrogen promoted the expansion of high-affinity antibody-producing B cells and also promoted survival by increasing expression of the Bcl-2 anti-apoptotic molecule Immune cells express PR and AR, and progesterone, androgen, and testosterone in particular are considered immuno-suppressive and may counteract the effects of estrogens, contributing to the observed increased susceptibility to the SARS-CoV-2 and disease in men 98 — Androgen receptor-deficient mice exhibit reduced numbers of neutrophils and accordingly increased susceptibility of male mice to SARS-CoV infection correlated with accumulation of neutrophils in the lung.

Progesterone reduces T-cell proliferation and T-cell-dependent antibody responses in human peripheral blood and cell line or mouse studies. Its effects on B cells included reduced class switch recombination and reduced T cell dependent antibody production. Normal testosterone levels are associated with normal respiratory capacity, whereas plasma testosterone levels decline in men with increasing age with observed associations between an increase of pro-inflammatory states and decline in testosterone in aging men.

On the other hand, high androgen levels may promote or contribute to infection because AR mediated transcription of TMPRSS2 protease which is important for viral entry into host cells. A proposed androgen sensitivity model provides a link between increased disease severity in men and the role of androgens in COVID Androgen sensitivity is primarily determined by genetic variants of the AR.

While men are generally predisposed to these effects due to higher testosterone levels compared to women, individuals with hyperandrogenism and other conditions may similarly be impacted. For example, women with hirsutism and polycystic ovarian syndrome PCOS , as well as women taking progesterone-based birth control, may be at greater risk for more severe COVID symptoms Markers of androgen sensitivity such as PCOS, androgenetic alopecia, and prostatic hyperplasia may thus be used as clinical signs of vulnerability.

In this pandemic, men are more acutely ill and exhibit higher death rates with disproportionately higher numbers in ICU and requiring ventilators compared to women. Even pregnant women had lower rates and less severe disease and complications than men. Estrogen and progesterone levels rise exponentially during pregnancy, causing a shift in the immune response, and this may underlie the observed protective effects.

The importance of these female sex hormones in the immune response to infections has triggered two clinical trials with sex hormone administration to patients with COVID Half will receive a single-use transdermal estradiol patch for 7 days, and the other half will serve as a control group and receive standard of care.

The second, smaller randomized controlled trial with 40 male patients at Cedars-Sinai hospital in Los Angeles will administer progesterone in an effort to suppress the overactive immune response and mitigate immunopathology. Inpatients with mild to moderate disease will be included and half will receive progesterone mg subcutaneous twice daily for 5 days, and the other half is a control group. Since progesterone is immune-suppressive and diminishes the proinflammatory response, this trial is intended to determine whether progesterone treatment can reduce the incidence of cytokine storm and related immunopathology leading to ARDS.

It is well-known that the commensal bacteria in the GI tract impact the immune response. Some possible mechanisms involve microbiota affecting and regulating cytokine production , while others involve microbiota modulation of the production of mucous and antiviral defensins and ROS In regard to viral infections, however, some microbiota elicit protective effects, while others serve as a route of viral entry and infection.

For example, the Lactobacillus genus prevents murine norovirus replication in vitro , and there is in vivo evidence that this genus is decreased in a mouse that is affected by norovirus. In response to Influenza and WNV, gut microbiota secrete IgA and upregulate TLR-7 in the respiratory mucosa in order to promote activation of important components of antiviral immunity—cytotoxic T lymphocytes, Th1 cells, and inflammasomes.

It is therefore possible that there is an interaction between these bacteria and the virus, though the exact relationship is unknown. One possible mechanism is that, similarly to the human norovirus, the normally commensal bacteria are harboring the virus and are producing a cytokine response that is inappropriate for the response to the infection. This ultimately would result in dysbiosis and a worse outcome for the patient. Alternatively, a relationship between ACE-2 and the gut microbiome may play a role in the immune response.

This protein is critical for the transportation of tryptophan across the epithelium, which then normally increases the production of antimicrobial peptides that affect the composition of the microbiome Lack of this peptide production would likely result in dysbiosis and an impaired immune response.

Recently, it has been noted that sex hormones have a large effect on the microbiome. Particularly, higher levels of systemic estrogen, like those seen in women, are positively associated with the richness and diversity of the fecal microbiome Additionally, germ-free female mice have higher baseline antibody levels than germ-free male mice Taken together, these studies suggest that female sex hormones, particularly estrogen, have a pro-inflammatory effect 4 that promotes a more robust response to infection.

In addition to lacking the stimulatory effects of estrogen, men also produce androgens that seem to have a protective mechanism against the immune response. Furthermore, the testosterone surge at puberty in male mice dampens B- and T-cell development Commensal bacteria in the gastrointestinal tract have a role in regulation of testosterone levels An in vivo study found that the number of species in microbiomes of mice was not significantly different during the pre-pubescent stage but was significantly different following puberty This suggests that hormone changes during puberty drive changes in the microbiome.

Further, the microbiome elevates androgens to a level that confers protection from type 1 diabetes in mice , , which illustrates the synergistic effect of the male hormones and the microbiome. While this is thought to be a major factor in the protection against autoimmunity, it is also reasonable to think that the immune response may be dampened below the level that is needed for a strong response to pathogens.

Overall, these findings suggest that the microbiome is an important biological factor in the sex-bias in response to infection and may be involved in the SARS-CoV-2 responses. This binding leads to the subsequent downregulation of ACE2, which is considered to be protective against lung injury. Stimulation of AGTR1a receptor by angiotensin II leads to endothelial cell permeability which may explain the increase in pulmonary pathology with decreasing levels of expressed ACE2.

The location of ACE2 on the X chromosome suggests possible genetic influence in the elevated male mortality rate. For example, mutations in ACE2 in one cell line may alter the catalytic site and lead to divergent viral susceptibilities between cell populations decreasing peak viral load Substitutions in these amino acids, among other mutations, may alter binding affinity between the RBD and receptor, limiting the ability of the virus to enter the cell and propagate.

Variable expression of ACE2 may also influence patient outcomes. Viral entry into a cell causes downregulation of ACE2, which may be detrimental in patients already deficient in ACE2 ACE2 downregulation leads to pulmonary edema, alveolus hyalinization, and leukocyte accumulation. Cecal ligation and perforation of ACE2 knockout mice has also been shown to increase lung failure and tissue damage, indicating that ACE2 may confer a protective role in microbial infection Gene dosage, however, likely does not contribute to the sex-based difference in SARS-CoV-2 response, as evidence suggests that sexual dimorphism in ACE2 expression persists in renal tissue but not cardiac or pulmonary tissue under non-pathological conditions Moreover, changes in chromosome dosage was not observed to affect ACE2 expression in mice that had undergone gonadorectomy.

This finding implies possible hormonal but not chromosomal effects in ACE2 expression levels. Despite limited evidence supporting the effect of chromosome dosage in the increased male mortality rate, cellular mosaicism in women may offer protection against immune deficiency.

As a result, the effect of detrimental mutations to ACE2 may be more pronounced in men than women, altering the clinical course in male versus female patient populations. The ACE2 receptor is expressed in the type II pneumocytes of the lungs and also in other tissues, including the heart, tubular epithelial cells in kidneys, testis, adipose tissue, and the enterocytes in the gastrointestinal tract and vascular endothelial cells A recent study evaluated ACE2 expression in older men and women with heart failure and found in two independent cohorts that circulating plasma concentrations of ACE2 were higher in men than in women This may reflect differences in tissues from men versus women.

Two studies utilized systems biology approaches of meta-analysis, co-expression and network analysis to draw information on the expression, regulation and gender bias of ACE2 receptor expression. The highest levels of ACE2 expression were found in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, medium levels in the lungs, colon, liver, bladder, and adrenal gland, and lowest in blood, spleen, bone marrow, brain, blood vessels, and muscle.

While they did not find a significant difference in gene expression between men and women, ACE2 expression in the lungs was positively correlated with immune signatures in men and negatively in women. In addition the HPA database showed high levels of both ACE2 gene and protein in the gastrointestinal tract duodenum, small intestine, colon, and rectum , kidney, gallbladder, and male tissues testis and seminal vesicle.

Taken together these data suggest that the differential host immune responses may underlie the gender-bias of the remarkably distinct clinical outcomes. The other study of patients with severe COVID who had comorbidities evaluated data from over lung transcriptome samples and found that ACE2 was highly expressed in these patients, compared to controls. Suggesting epigenetic regulation of ACE2 in the human lung. ACE2 is known to be expressed in Leydig cells of both mice and humans, albeit testosterone-independent, and is thought to contribute to steroid synthesis , It is also expressed in ovarian granulosa cells and its levels increase in correlation with increasing LH levels.

In addition to expression in the gonads, ACE2 expression and activity is influenced by sex hormones in adipose tissue, myocardium, and kidneys. Higher ACE and ACE2 activity and cardiac hypertrophy was found in male rats compared to female rats which was reduced after orchiectomy, while ovariectomy elevated ACE2 and hypertrophy in females In female mice, HFD increased adipose tissue ACE2 which was reversed by ovariectomy implying that estrogen increases ACE2 expression and activity in adipose tissue and kidneys.

Importantly, ovariectomy or treatment with an ER antagonist in SARS-CoV infected female mice increased the mortality rate therefore, suggesting a protective effect for the ER signaling pathway in mice 3. While sex hormones influence ACE2 expression and activity to influence outcomes in obesity, hypertension, and related comorbidities, thus influencing COVID outcomes, the effect of COVID on male sex hormones has been recently explored.

Given that the ACE2 receptor is expressed in the testes, a study from Hubei province of China reports that the COVID impacts male gonadal function and observed alterations in hormone levels. They studied 81 men with COVID and found that serum luteinizing hormone LH levels were increased while the ratio of testosterone to LH and the ratio of follicle stimulating hormone FSH to LH were significantly lower compared with age-matched healthy men Recent reports of increased frequency of venous thromboembolism, associated with worse outcomes in patients with COVID warrant caution in treatment with testosterone, specifically in hypogonadal men with greater genetic predisposition.

Besides its role in infection immunity, sex is equally important in the immune response to vaccines , Women not only mount stronger antibody and T-cell responses to vaccinations than men, but also suffer more adverse events. Yet there is a serious lack of attention to gender in vaccine trials. This leads to inappropriate dosage of vaccines as evidenced by the fact that the same magnitude of protective immunity is achieved by half the dose of seasonal influenza vaccine in women compared to men.

Likewise, these gender-blind vaccination strategies lead to increased adverse effects in women. Increased hospitalizations and mortality have been observed in female infants and girls following DPT, measles and oral polio vaccinations Sex-based biological factors include differences across the immune system within innate immunity, antibody responses and T cell responses.

Genetics, sex hormones, epigenetic factors, nutrition, and the microbiome are important biological contributors to these sex-based differences. Vaccine-related research and clinical trials, including those currently underway for COVID, must thus include sex as a key variable when measuring and reporting outcomes of immunogenicity and reactogenicity. This information would help tailor vaccine dosage and strategies appropriately to maximize protective immunity while minimizing adverse effects.

The COVID pandemic has revealed a striking gender-bias with increased case and mortality rates in men compared with women across the lifespan. Besides behavioral and lifestyle factors, sex-based physiological differences influence the host immune response to infections.

Sex chromosome linked genes, sex hormones, and the microbiome control aspects of the innate and adaptive immune responses to infection. Better understanding of these factors is necessary to tailor therapies and vaccine strategies in a step toward sex-based personalized medicine.

VM conceptualized the article. All authors contributed to the literature review, writing, and finalizing the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Dr. Robert Shmerling for critical review of the manuscript and helpful suggestions.

COVID infection: the perspectives on immune responses. Cell Death Differ. Clinical characteristics of coronavirus disease in China. New Engl J Med. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol. Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells.

Intensive Care Med. David R. Are men and women different? Nat Rev Immunol. Int J Mol Sci. Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin Immunopathol.

Cell Host Microbe. Response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology. J Gen Virol. Chemokine CXCL1 mediated neutrophil recruitment: role of glycosaminoglycan interactions. Sci Rep.

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Knowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function s , interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 IDO1 is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells pDCs , thus activating genomic effects, ultimately leading to long-lasting immunosuppression.

Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases PI3Ks , which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events.

Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity. A cell-based bioluminescence assay reveals dose-dependent and contextual repression of APdriven gene expression by BACH2. Whereas effector CD4 and CD8 T cells promote immune activation and can drive clearance of infections and cancer, CD4 regulatory T T cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression.

The transcription factor BACH2 functions as a pervasive regulator of T cell differentiation, promoting development of CD4 T cells and suppressing the effector functions of multiple effector T cell T lineages. Here, we report the development of a stable cell-based bioluminescence assay of the transcription factor activity of BACH2.

BACH2 expression repressed the luciferase signal in a dose-dependent manner but this activity was abolished at high levels of AP-1 signalling, suggesting contextual regulation of AP-1 driven gene expression by BACH2. Scientific reports, 10, 1, , 03 Nov Science signaling, 13, , , 03 Nov Alternative systems for misfolded protein clearance: life beyond the proteasome. Protein misfolding is a major driver of ageing-associated frailty and disease pathology.

Although all cells possess multiple, well-characterised protein quality control systems to mitigate the toxicity of misfolded proteins, how they are integrated to maintain protein homeostasis 'proteostasis' in health-and how their dis-integration contributes to disease-is still an exciting and fast-paced area of research. Under physiological conditions, the predominant route for misfolded protein clearance involves ubiquitylation and proteasome-mediated degradation.

When the capacity of this route is overwhelmed-as happens during conditions of acute environmental stress, or chronic ageing-related decline-alternative routes for protein quality control are activated. In this review, we summarise our current understanding of how proteasome-targeted misfolded proteins are re-trafficked to alternative protein quality control routes such as juxta-nuclear sequestration and selective autophagy when the ubiquitin-proteasome system is compromised.

We also discuss the molecular determinants of these alternative protein quality control systems, attempt to clarify distinctions between various cytoplasmic spatial quality control inclusion bodies e. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed.

VM in which the year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting a a high phenotypic variability with in some cases isolated manifestations, b the potential of adult-onset disease, and c a novel manifestation with ANCA-associated vasculitis.

Frontiers in immunology, 11, 1, , Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells MuSCs. A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles EOM have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined.

Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues.

These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine. PLoS genetics, 16, 10, , 30 Oct Developmental cell, 55, 2, , 26 Oct Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome.

To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. High level MMTVdriven transgenic expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. High-resolution three-dimensional chromatin profiling of the Chinese hamster ovary cell genome.

Chinese hamster ovary CHO cell lines are the pillars of a multi-billion dollar biopharmaceutical industry producing recombinant therapeutic proteins. The effects of local chromatin organisation and epigenetic repression within these cell lines result in unpredictable and unstable transgene expression following random integration. Limited knowledge of the CHO genome and its higher-order chromatin organisation has thus far impeded functional genomics approaches required to tackle these issues.

Our genome-wide 3D map identifies higher-order chromatin structures such as topologically associated domains, incorporates our chromatin accessibility data to enhance the identification of active cis-regulatory elements and importantly links these cis-regulatory elements to target promoters in a 3D promoter interactome.

We demonstrate the power of our improved functional annotation by evaluating the 3D landscape of a transgene integration site and two phenotypically different cell lines. Our work opens up further novel genome engineering targets, has the potential to inform vital improvements for industrial biotherapeutic production, and represents a significant advancement for CHO cell line development. This article is protected by copyright. All rights reserved.

Biotechnology and bioengineering, 1, 1, , 23 Oct The mechanisms by which regulatory T Treg cells differentially control allergic and autoimmune responses remain unclear. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses.

The role of ZFP57 and additional KRAB-zinc finger proteins in the maintenance of human imprinted methylation and multi-locus imprinting disturbances. Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders IDs displays multi-locus imprinting disturbances MLID , which may result from aberrant establishment of imprinted differentially methylated regions DMRs in gametes or their maintenance in early embryogenesis.

By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins KZNFs recruit KAP1 prior to blastocyst formation.

Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect. Nucleic acids research, 1, 1, , 14 Oct A comprehensive and standardized system to report lipid structures analyzed by mass spectrometry is essential for the communication and storage of lipidomics data.

Finally, annotation of atoms is included for the use of stable isotope-labelled compounds in metabolic labelling experiments or as internal standards. This update on lipid classification, nomenclature and shorthand annotation for lipid mass spectra is considered a standard for lipid data presentation.

Journal of lipid research, 1, 1, , 09 Oct Decreased expression of miR family associated with autoimmune myasthenia gravis. Myasthenia gravis MG is a rare autoimmune disease mainly mediated by autoantibodies against the acetylcholine receptor AChR at the neuromuscular junction.

The thymus is the effector organ, and its removal alleviates the symptoms of the disease. In the early-onset form of MG, the thymus displays functional and morphological abnormalities such as B cell infiltration leading to follicular hyperplasia, and the production of AChR antibodies. Journal of neuroinflammation, 17, 1, , 08 Oct LipidFinder 2. We present LipidFinder 2. We also incorporate a novel false discovery rate FDR method, utilizing a target-decoy strategy, which allows users to assess data quality.

A renewed lipid profiling method is introduced which searches three different databases from LIPID MAPS and returns bulk lipid structures only, and a lipid category scatter plot with color blind friendly pallet. We show using real data that LipidFinder 2. Bioinformatics Oxford, England , 1, 1, , 07 Oct Active turnover of DNA methylation during cell fate decisions. DNA methylation is a key layer of epigenetic regulation.

The deposition of methylation marks relies on the catalytic activity of DNA methyltransferases DNMTs , and their active removal relies on the activity of ten-eleven translocation TET enzymes. Paradoxically, in important biological contexts these antagonistic factors are co-expressed and target overlapping genomic regions. The ensuing cyclic biochemistry of cytosine modifications gives rise to a continuous, out-of-thermal equilibrium transition through different methylation states.

But what is the purpose of this intriguing turnover of DNA methylation? Recent evidence demonstrates that methylation turnover is enriched at gene distal regulatory elements, including enhancers, and can give rise to large-scale oscillatory dynamics.

We discuss this phenomenon and propose that DNA methylation turnover might facilitate key lineage decisions. Nature reviews. Genetics, 1, 1, , 06 Oct Although there is ample evidence that the advanced glycation end-product AGE glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane.

We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch's membrane, and choroid: all regions of the eye impacted by age-related macular degeneration.

Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.

ACS chemical biology, 1, 1, , 07 Oct Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis.

Genome-wide methylation sequencing of paired samples of colon normal adjacent, primary tumour and lymph node metastasis showed global hypomethylation and CpG island CGI hypermethylation of primary tumours compared to normal.

In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.

ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Annals of clinical and translational neurology, 1, 1, , 19 Sep Single-cell bisulfite sequencing scBS-seq enables profiling of DNA methylation at single-nucleotide resolution and across all genomic features.

It can explore methylation differences between cells in mixed cell populations and profile methylation in very rare cell types, such as mammalian oocytes and cells from early embryos. Here, we outline the scBS-seq protocol in a well plate format applicable to studies of moderate throughput. Inflammatory aortitis in a patient with type 2 hyper IgM syndrome. Rheumatology Oxford, England , 1, 1, , 17 Sep Personalized medicines require understanding the molecular causes of disease.

The work highlights how biochemistry can inform therapies to resolve complex immune disorders. LifeTime and improving European healthcare through cell-based interceptive medicine. LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease.

Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

International journal of molecular sciences, 21, 17, , 25 Aug SBML Level 3: an extensible format for the exchange and reuse of biological models. Systems biology has experienced dramatic growth in the number, size, and complexity of computational models.

To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models.

The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Molecular systems biology, 16, 8, , Aug Imprints in the history of epigenetics. Kelsey G. Molecular cell biology, 1, 1, , 24 Aug Hypermethylation and reduced expression of Gtl2, Rian and Mirg at the Dlk1-Dio3 imprinted locus as a marker for poor developmental potential of mouse embryonic stem cells. Mouse embryonic stem cells ESCs have played a crucial role in biomedical research where they can be used to elucidate gene function through the generation of genetically modified mice.

A critical requirement for the success of this technology is the ability of ESCs to contribute to viable chimaeras with germ-line transmission of the genetically modified allele. We have identified several ESC clones that cause embryonic death of chimaeras at mid to late gestation stages. These clones had a normal karyotype, were pathogen free and their in vitro differentiation potential was not compromised.

Chimaeric embryos developed normally up to E We investigated the relationship between the ESCs transcriptional and epigenomic state and their ability to contribute to viable chimaeras. Bisulphite sequencing analysis showed significant hypermethylation at the Dlk1-Dio3 imprinted locus with no consistent differences in methylation patterns at other imprinted loci.

Treatment of the compromised ESCs with 5-azacytidine reactivated stable expression of Gtl2 and rescued the lethal phenotype but only gave low level chimaeras. Stem cell research, 48, 1, , 29 Jul Cbls boost B cells. Linterman MA. T cell regulation of antibody-mediated immunity is critical for health. In this issue of JEM, Li et al. The Journal of experimental medicine, , 9, , 07 Sep Variability among pluripotent stem cell PSC lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy.

This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability.

This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt pathway, which is modulated by specific genetic variants. Overall, this study shows that genetic background plays a dominant role in driving phenotypic variability of PSCs.

Cell stem cell, 1, 1, , 11 Aug The molecular bases for E2-E3 Ub transfer and Ub relay are unknown. Whether these activities are linked to the neural phenotypes is also unclear. Furthermore, neurodevelopmental defects and delayed injury-induced degeneration in RCR-defective knock-in mice suggest its requirement, and that of substrate esterification activity, for normal neural development and programmed axon degeneration.

Nature chemical biology, 1, 1, , 03 Aug Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response DDR associated with cell death occur in Tregs in individuals with autoimmunity.

In an experimental autoimmune encephalitis EAE mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance.

Cell metabolism, 1, 1, , 22 Jul DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors HIFs , but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia. Genome Biology, 21, 1, , 27 Jul The brain is a site of relative immune privilege. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome.

This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. Epigenetic reprogramming is a cancer hallmark, but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. We identify a dichotomy between bivalent genes that do and do not become hypermethylated, which is also mirrored in cancer. We find that loss of H3K4me3 at bivalent regions is associated with gain of methylation.

Nature communications, 11, 1, , 22 Jul It is currently assumed that 3D chromosomal organization plays a central role in transcriptional control. However, depletion of cohesin and CTCF affects the steady-state levels of only a minority of transcripts.

Here, we use high-resolution Capture Hi-C to interrogate the dynamics of chromosomal contacts of all annotated human gene promoters upon degradation of cohesin and CTCF. We show that a majority of promoter-anchored contacts are lost in these conditions, but many contacts with distinct properties are maintained, and some new ones are gained.

The rewiring of contacts between promoters and active enhancers upon cohesin degradation associates with rapid changes in target gene transcription as detected by SLAM sequencing SLAM-seq. These results provide a mechanistic explanation for the limited, but consistent, effects of cohesin and CTCF depletion on steady-state transcription and suggest the existence of both cohesin-dependent and -independent mechanisms of enhancer-promoter pairing.

Cell reports, 32, 3, , 21 Jul Michael John Owen Wakelam Michael John Owen Wakelam passed away on 31 March, at the age of 64, much too early. He became known to colleagues and friends as a scientist highly regarded for his research. He was honoured in with the Morton Lectureship of the Biochemical Society and was elected a fellow of the Royal Society of Biology. In , he was elected a member of the Academia Europaea. Nature metabolism, 2, 6, , Jun Morf J, Wingett SW.

RNA localization is an important regulatory layer of gene expression and cell functioning. The protocol guides through the Proximity RNA-seq method, in which RNA molecules are sequenced in their spatial, cellular context to derive RNA co-localization and transcriptome organization. Transcripts in individual subcellular particles from chemically crosslinked cells are tagged with the same, unique DNA barcode in water-in-oil emulsion droplets. Subsequently, 3' ends of bead-bound barcode copies are tailed with random pentadecamers.

Then beads are encapsulated again into droplets together with crosslinked subcellular particles containing RNA. Reverse transcription using random pentadecamers as primers is performed in droplets, which optimally contain one bead and one particle, in order to tag RNAs co-localized to the same particle.

Subsequent analysis of transcripts that share the same barcode, i. The technique is not restricted to pairs of RNAs but can as well detect groups of transcripts and estimates local RNA density or connectivity for individual transcripts. We provide here a detailed protocol to perform and analyze Proximity RNA-seq on cell nuclei to study spatial, nuclear RNA organization. Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects.

Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation.

Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure. Cell reports, 32, 2, , 14 Jul Zygotic genome activation ZGA is an essential transcriptional event in embryonic development that coincides with extensive epigenetic reprogramming.

Complex manipulation techniques and maternal stores of proteins preclude large-scale functional screens for ZGA regulators within early embryos. Follow-up assays validated top screen hits, including the DNA-binding protein Dppa2, the chromatin remodeler Smarca5, and the transcription factor Patz1, and functional experiments revealed that Smarca5's regulation of ZGA-like transcription is dependent on Dppa2. Together, our single-cell transcriptomic profiling of CRISPRa-perturbed cells provides both system-level and molecular insights into the mechanisms that orchestrate ZGA.

Systems biology markup language SBML level 3 package: multistate, multicomponent and multicompartment species, version 1, release 2. Rule-based modeling is an approach that permits constructing reaction networks based on the specification of rules for molecular interactions and transformations. These rules can encompass details such as the interacting sub-molecular domains and the states and binding status of the involved components.

Conceptually, fine-grained spatial information such as locations can also be provided. Through "wildcards" representing component states, entire families of molecule complexes sharing certain properties can be specified as patterns. This can significantly simplify the definition of models involving species with multiple components, multiple states, and multiple compartments.

Therefore, reaction rules may contain species that can be patterns and exist in multiple locations. Multiple software tools such as Simmune and BioNetGen support this standard that thus also becomes a medium for exchanging rule-based models. No design changes have been made to the description of models between Release 1 and Release 2; changes are restricted to the correction of errata and the addition of clarifications. Journal of integrative bioinformatics, 1, 1, , 06 Jul Genomic imprinting is an epigenetic phenomenon leading to parental allele-specific expression.

Dosage of imprinted genes is crucial for normal development and its dysregulation accounts for several human disorders. This unusual expression pattern is mostly dictated by differences in DNA methylation between parental alleles at specific regulatory elements known as imprinting control regions ICRs. Although several approaches can be used for methylation inspection, we lack an easy and cost-effective method to simultaneously measure DNA methylation at multiple imprinted regions.

We adapted amplicon bisulfite-sequencing protocols to design IMPLICON for ICRs in adult tissues of inbred mice, validating it in hybrid mice from reciprocal crosses for which we could discriminate methylation profiles in the two parental alleles. We also provide rules and guidelines to adapt this method for investigating the DNA methylation landscape of any set of genomic regions. Nucleic acids research, 1, 1, , 04 Jul Replicative aging is associated with loss of genetic heterogeneity from extrachromosomal circular DNA in Saccharomyces cerevisiae.

Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA rDNA accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y' regions.

In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age. Nucleic acids research, 1, 1, , 01 Jul Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes. The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones.

We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I. Correction to: DNA methylation changes during preimplantation development reveal interspecies differences and reprogramming events at imprinted genes.

An amendment to this paper has been published and can be accessed via the original article. Clinical epigenetics, 12, 1, , 29 Jun The receptor-linked protein tyrosine phosphatases RPTPs are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels.

Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal D1 domain and an inactive distal D2 pseudophosphatase domain. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine.

Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal "backdoor" cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.

Nature communications, 11, 1, , 26 Jun BioModels Parameters: a treasure trove of parameter values from published systems biology models. One of the major bottlenecks in building systems biology models is identification and estimation of model parameters for model calibration. Searching for model parameters from published literature and models is an essential, yet laborious task.

Bioinformatics Oxford, England , 1, 1, , 23 Jun Epigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment. How the epigenetic landscape is established in development is still being elucidated. Our findings uncover a novel epigenetic priming mechanism at developmental promoters, poising them for future lineage-specific activation.

Mechanical stretching changes cross-linking and glycation levels in the collagen of mouse tail tendon. Collagen I is a major tendon protein whose polypeptide chains are linked by covalent cross-links. It is unknown how the cross-linking contributes to the mechanical properties of tendon or whether cross-linking changes in response to stretching or relaxation.

Since their discovery, imine bonds within collagen have been recognized as being important in both cross-link formation and collagen structure. They are often described as acidic or thermally labile, but no evidence is available from direct measurements of cross-link levels whether these bonds contribute to the mechanical properties of collagen. Here, we used MS to analyze these imine bonds after reduction with sodium borohydride while under tension and found that their levels are altered in stretched tendon.

We also noted a decrease in glycated lysine residues in collagen, indicating that the imine formed between circulating glucose and lysine is also stress-labile. The results from both the MS studies and mechanical testing provide insights into the chemical changes during tendon stretching and directly link these chemical changes to functional collagen properties. The Journal of biological chemistry, 1, 1, , 16 Jun This protocol obtains precise measurements of gene expression from single worms or from bulk samples.

It increases experimental throughput by allowing the preparation of cDNA from 96 worms in 3. This paper evaluates two different nanofluidic chips: the first runs 96 samples and 96 targets, resulting in 9, reactions in approximately 1. The second chip type consists of six 12 x 12 arrays, resulting in reactions. Here, the Worm-to-CT method is demonstrated by quantifying mRNA levels of genes encoding heat shock proteins from single worms and from bulk samples.

Provided is an extensive list of primers designed to amplify processed RNA for the majority of coding genes within the C. Journal of visualized experiments : JoVE, 1, , , 28 May An issue often encountered when acquiring image data from fixed or anesthetized C. This problem is aggravated with increasing density of worms and creates challenges for imaging and quantification.

We developed a FIJI-based workflow, Worm-align, that can be used to generate single- or multi-channel montages of user-selected, straightened and aligned worms from raw image data of C. Worm-align is a simple and user-friendly workflow that does not require prior training of either the user or the analysis algorithm. Montages generated with Worm-align can aid the visual inspection of worms, their classification and representation.

In addition, the output of Worm-align can be used for subsequent quantification of fluorescence intensity in single worms, either in FIJI directly, or in other image analysis software platforms. CellProfiler's flexibility enables the incorporation of additional modules for high-content screening.

As a practical example, we have used the pipeline on two datasets: the first dataset are images of heat shock reporter worms that express green fluorescent protein GFP under the control of the promoter of a heat shock inducible gene hsp, and the second dataset are images obtained from fixed worms, stained for fat-stores with a fluorescent dye. Axon Degeneration: Which Method to Choose? Coleman MP. Axons are diverse. They have different lengths, different branching patterns, and different biological roles.

Methods to study axon degeneration are also diverse. The result is a bewildering range of experimental systems in which to study mechanisms of axon degeneration, and it is difficult to extrapolate from one neuron type and one method to another. The purpose of this chapter is to help readers to do this and to choose the methods most appropriate for answering their particular research question. BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression.

Regulatory T Treg cell populations are composed of functionally quiescent resting Treg rTreg cells which differentiate into activated Treg aTreg cells upon antigen stimulation. How rTreg cells remain quiescent despite chronic exposure to cognate self- and foreign antigens is unclear. The transcription factor BACH2 is critical for early Treg lineage specification, but its function following lineage commitment is unresolved. Here, we show that BACH2 is repurposed following Treg lineage commitment and promotes the quiescence and long-term maintenance of rTreg cells.

Bach2 is highly expressed in rTreg cells but is down-regulated in aTreg cells and during inflammation. This function promotes rTreg cell quiescence and long-term maintenance and is required for immune homeostasis and durable immunosuppression in cancer. Thus, BACH2 supports a "division of labor" between quiescent rTreg cells and their activated progeny in Treg maintenance and function, respectively.

A distal enhancer at risk locus 11q Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro.

Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3 T cells, which are unable to control colitis in a cell-transfer model of the disease. In human T cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression.

Finally, functional fine-mapping of 11q These findings provide a mechanistic basis for association of the 11q Active and repressed biosynthetic gene clusters have spatially distinct chromosome states. While colocalization within a bacterial operon enables coexpression of the constituent genes, the mechanistic logic of clustering of nonhomologous monocistronic genes in eukaryotes is not immediately obvious.

Biosynthetic gene clusters that encode pathways for specialized metabolites are an exception to the classical eukaryote rule of random gene location and provide paradigmatic exemplars with which to understand eukaryotic cluster dynamics and regulation. Here, using 3C, Hi-C, and Capture Hi-C CHi-C organ-specific chromosome conformation capture techniques along with high-resolution microscopy, we investigate how chromosome topology relates to transcriptional activity of clustered biosynthetic pathway genes in Our analyses reveal that biosynthetic gene clusters are embedded in local hot spots of 3D contacts that segregate cluster regions from the surrounding chromosome environment.

The spatial conformation of these cluster-associated domains differs between transcriptionally active and silenced clusters. We further show that silenced clusters associate with heterochromatic chromosomal domains toward the periphery of the nucleus, while transcriptionally active clusters relocate away from the nuclear periphery. Examination of chromosome structure at unrelated clusters in maize, rice, and tomato indicates that integration of clustered pathway genes into distinct topological domains is a common feature in plant genomes.

Our results shed light on the potential mechanisms that constrain coexpression within clusters of nonhomologous eukaryotic genes and suggest that gene clustering in the one-dimensional chromosome is accompanied by compartmentalization of the 3D chromosome. LPS-treatment of bovine endometrial epithelial cells causes differential DNA methylation of genes associated with inflammation and endometrial function.

Lipopolysaccharide LPS endotoxin stimulates pro-inflammatory pathways and is a key player in the pathological mechanisms involved in the development of endometritis. BMC genomics, 21, 1, , 03 Jun The dead phosphatases society: a review of the emerging roles of pseudophosphatases. Phosphatases are a diverse family of enzymes, comprising at least 10 distinct protein folds. Like most other enzyme families, many have sequence variations that predict an impairment or loss of catalytic activity classifying them as pseudophosphatases.

Research on pseudoenzymes is an emerging area of interest, with new biological functions repurposed from catalytically active relatives. Here, we provide an overview of the pseudophosphatases identified to date in all major phosphatase families.

We will highlight the degeneration of the various catalytic sequence motifs and discuss the challenges associated with the experimental determination of catalytic inactivity. We will also summarize the role of pseudophosphatases in various diseases and discuss the major challenges and future directions in this field. Traumatic brain injury is a major global cause of death and disability.

Axonal injury is a major underlying mechanism of TBI and could represent a major therapeutic target. We provide evidence that targeting the axonal death pathway known as Wallerian degeneration improves outcome in a model of high impact trauma. This cell-autonomous neurodegenerative pathway is initiated following axon injury, and in Drosophila, involves activity of the E3 ubiquitin ligase. We demonstrate that a loss-of-function mutation in the gene rescues deleterious effects of a traumatic injury, including-improved functional outcomes, lifespan, survival of dopaminergic neurons, and retention of synaptic proteins.

This data suggests that represents a potential therapeutic target in traumatic injury. Frontiers in neurology, 11, 1, , A distinctive epigenetic ageing profile in human granulosa cells. Human reproduction Oxford, England , 1, 1, , 31 May The ten-eleven translocation factor TET1 and its conferred epigenetic modification 5-hydroxymethylcytosine 5hmC have important roles in maintaining the pluripotent state of embryonic stem cells ESCs.

Here, we establish an integrated panel of absolute 5hmC levels, genome-wide DNA methylation and hydroxymethylation patterns, transcriptomes, and TET1 chromatin occupancy in TSCs and differentiated trophoblast cells. We show that the combined presence of 5-methylcytosine 5mC and 5hmC correlates with transcriptional activity of associated genes.

Hypoxia can slow down the global loss of 5hmC that occurs upon differentiation of TSCs. These chromatin modification and occupancy patterns are highly informative to identify novel candidate regulators of the TSC state. Stem cell reports, 1, 1, , 13 May Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidemia by increased energy expenditure.

We sought to investigate this discordance. Molecular metabolism, 1, 1, , 18 May THP-1 macrophage cholesterol efflux is impaired by palmitoleate through Akt activation. Lipoprotein lipase LPL is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins.

Notably, the free fatty acid FFA component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation.

This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation.

Remodeling of light and dark zone follicular dendritic cells governs germinal center responses. Efficient generation of germinal center GC responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells BRCs. How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle.

Here we used genetic targeting of Cxclexpressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCLdependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells.

Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction. Nature immunology, 1, 1, , 18 May Senescence blurs the line between innate and adaptive immune cells.

In Covre et al. Immunology and cell biology, 1, 1, , 13 May DNA methylation changes during preimplantation development reveal inter-species differences and reprogramming events at imprinted genes. Preimplantation embryos experience profound resetting of epigenetic information inherited from the gametes. Genome-wide analysis at single-base resolution has shown similarities but also species differences between human and mouse preimplantation embryos in DNA methylation patterns and reprogramming.

Here, we have extended such analysis to two key livestock species, the pig and the cow. We generated genome-wide DNA methylation and whole-transcriptome datasets from gametes to blastocysts in both species. In oocytes from both species, a distinctive bimodal methylation landscape is present, with hypermethylated domains prevalent over hypomethylated domains, similar to human, while in the mouse the proportions are reversed.

An oocyte-like pattern of methylation persists in the cleavage stages, albeit with some reduction in methylation level, persisting to blastocysts in cow, while pig blastocysts have a highly hypomethylated landscape. In the pig, there was evidence of transient de novo methylation at the cell stages of domains unmethylated in oocytes, revealing a complex dynamic of methylation reprogramming. The methylation datasets were used to identify germline differentially methylated regions gDMRs of known imprinted genes and for the basis of detection of novel imprinted loci.

Strikingly in the pig, we detected a consistent reduction in gDMR methylation at the cell stages, followed by recovery to the blastocyst stage, suggesting an active period of imprint stabilization in preimplantation embryos. Transcriptome analysis revealed absence of expression in oocytes of both species of ZFP57, a key factor in the mouse for gDMR methylation maintenance, but presence of the alternative imprint regulator ZNF In conclusion, our study reveals species differences in DNA methylation reprogramming and suggests that porcine or bovine models may be closer to human in key aspects than in the mouse model.

Clinical epigenetics, 12, 1, , 11 May Radiographic findings most commonly included atypical pneumonia with bilateral, peripheral, and posterior features. Chest CT findings include ground-glass opacities and bilateral consolidation in more than half of admitted patients 2.

Patients with features of these abnormal laboratory findings were most likely in cases of severe disease. Although a plethora of information has been published recently on symptoms, signs, and pathology in COVID disease, little information has been stratified by sex differences.

Optimistically, cognizance that these dimorphisms exist will give rise to novel research and therapies that take advantage of these differences. Dendritic cells DC are the primary antigen-presenting cells APC of the human body and are divided into myeloid or lymphoid types based on their visual characteristics.

The current theory behind these conflicting findings is that the timing and level of IFN release is critical to its effect on the host. Plasmacytoid dendritic cells are responsible for coordinating an early IFN signal, which seems to be associated with better outcomes. This mechanism has been studied to reveal sex-based differences in signaling. Male mice had higher rates of vascular leakage, leading to alveolar edema, and a study of bronchoalveolar lavage fluid 3 days after infection showed they had 4—5x higher rates of neutrophils compared to female mice.

However, maintaining a balance in the level of PMNs is critical, as PMNs can also cause pathological states in the host. In the same study, an overly increased presence of PMNs in a coronavirus rat model was found to be correlated with lung tissue inflammation, epithelial cell permeability, and hemorrhagic lesions It seems that in rats, male PMNs have higher rates of apoptosis compared to females, and apoptosis recruits phagocytic cells to the site of cell death 16 , The eosinophil response in SARS is largely unexplored, especially as it pertains to sex differences.

There is, however, convincing evidence that female sex hormones are strong activators of eosinophils. Estrogen promotes eosinophil development, adhesion, and degranulation. Eosinophil numbers spike when female rats have higher estrogen levels, and surgical excision of rat ovaries results in a sharp decrease in uterine eosinophils Eosinophil-derived neurotoxin is a key protein found in eosinophil granules and has strong ribonuclease activity especially when activated by proinflammatory stimuli.

Differences in EDN expression have not yet been analyzed in males vs. Basophils are the rarest of the granulocytes, and study of the basophil response to coronaviruses is even more unknown than eosinophil interactions. In one study, the incubation of human basophils with mild strains of coronavirus did not cause the leukocytes to degranulate or release histamine More studies are needed, however, to establish that basophils are not involved in the coronavirus response or that there are no sex-related differences in their interactions.

Mast cells reside in the submucosal layers of the respiratory tract; although they are mainly known for their functions in allergy responses, mastocytes are also intimately involved in protection from viral invaders In fact, their roles and activation in the immune response are incredibly interesting in the context of sex bias. It seems that, although mast cells from female mice bear granules with higher enymatic activity, these cells are activated to a lesser degree via the complement system than mast cells from male mice.

This may explain the increased preponderance of lung injury in men with coronavirus infection. Even when controlling for differences in number and extent of activation, mast cells from female mice make, store, and secrete more histamine than mastocytes of male origin. Gene analysis study has shown that genes such as Tnf, Hexa , and several mcpt genes that encode these intracellular granule mediators are upregulated in female mice. Mast cells from women store this increase in protein product by increasing the packing density of granules in mast cells This set of studies was repeated in the presence of various levels of female sex hormones, as previous literature has shown that the menstrual cycle can affect properties of mast cells in rodent models.

The study found that there was no statistically significant difference in the amount of histamine that mast cells released across levels of sex hormones in male and female mice This shows that while previous studies may point to significant hormonal effects on mast cell properties, there are sex-based differences in mastocyte biology that are not attributable to hormone interaction.

Mastocytes in the context of SARS-CoV infection are intimately involved with the complement system, which has significant proinflammatory responses that can result in pathological states. In fact, coronavirus infection activates the classical, the lectin, and the alternative pathways of the complement system. Of particular interest are C3 and C5 proteins which activate mast cell degranulation in SARS to trigger a cytokine storm 19 , This cytokine storm can lead to further downstream effects such as hyperemia and vascular permeability, which can result in acute, fatal lung injury.

In a similar vein, inhibition of the complement cascade via inhibition of C3 in Minfected mice results in less recruitment of neutrophils and inflammatory monocytes to the lung tissue The conclusion that reduced activation of the complement cascade results in maintenance of healthy lung tissue correlates to the sex bias found in levels of complement proteins. A recent study of 50, racially diverse subjects found that, compared to men, women have significantly lower levels of C4, an activator of C3.

In an investigation of Caucasian populations, levels of C3, C5, C7, C8, and C9 were significantly lower in women compared to men. Also women had lower amounts of proinflammatory positive regulators of the cascade such as properdin, mannan-binding lectin MBL , and Ficolin-3 These reduced levels of complement proteins were found to control activity of the whole cascade and its terminal products for the classical, lectin, and alternative pathways that are involved in SARS infection 20 , Yet, from both studies it is justifiable to say that the female host has mechanisms to reduce proinflammatory effects even with more potent mastocytes.

In the context of SARS, these techniques may prove useful if they are an explanation for the minimized incidence of pulmonary injury. In the discussion of pDC, it was iterated that the role and clinical effects of Type I IFN are still incompletely understood and are often conflicting across various studies. For example, Type I IFN administration 6 h post-infection before viral peak in mice infected with SARS coronavirus completely protected them from clinical disease 10 , Elevated and extended exposure of the host to IFN, however, led to excessive proinflammatory pathways and pulmonary pathology.

In the same study, mice were exposed to IFN post-peak of viral titers which resulted in lethal pathology. This acute lung injury in mice and humans with SARS is characterized by the presence of IFN-stimulated inflammatory monocyte-macrophages IMM and their associated proinflammatory cytokines in bronchoalveolar lavage fluid 10 — Although women have higher activation of IFN pathways early in coronavirus infections, it is unknown if there is a difference in IFN levels between men and women after peak viral load.

It may be that early activation of antiviral pathways more effectively reduces viral load by priming the innate and adaptive immune systems. This early activation can better protect the host from the cytokine storm found mostly in males that is associated with later IFN secretion 10 , 12 , Just three days post infection, there were 2—3-fold greater numbers of these IMM IL-6 is an activator of CCL2 binding to CCR2 which promotes lymphoid and myeloid chemotaxis as well as properties of leukocyte adhesion, polarization, secretion, and survival in the immune responses 12 , Additionally, use of monoclonal antibodies has also been considered for therapy in humans.

Natural Killer NK cells are cytotoxic lymphocytes of the innate immune system that target cancerous and infected cells. There is a plethora of puzzling information about the sex bias in NK cells. Some studies have found greater numbers and activity of NK cells from male rodents compared with females 4 , Another study of healthy geriatric individuals found that while there was an initial surplus of NK cells in men less than 70 years of age, there was a steep increase and superiority in NK cell function in women over 70 years 17 , This post-menopausal finding seems to defy other studies that found a rise in NK cells during the periovulatory phase when estrogen and progesterone are increased 4 , It is possible, however, that even if estrogen derivatives increase the number of NK cells, the cytotoxic capabilities of these cells may be reduced.

In contrast, Th2 cells produce cytokines that are more anti-inflammatory and redirect focus to humoral immunity mechanisms. The homeostasis between Th1 and Th2 cells is vital for the obliteration of infectious microbes without causing pathological states in the host. The SARS coronavirus of is notable in that it exclusively produced an activation of Th1 cells and cytokines in the host.

These protein levels were elevated for at least 2 weeks after onset and were sufficient for full recovery of the host. Across several studies, induction of anti-inflammatory Th2 pathways was not necessary for host survival 30 — The novel coronavirus SARS-CoV-2, however, seems to work differently when compared to its older relative, as sufficient induction of anti-inflammatory Th2 response is necessary.

Levels of these cytokines were much lower in non-ICU patients and the control group 32 , indicating that pathogenic Th1 cells correlate with the hyper-inflammatory response in SARS-CoV-2 pathogenesis. Physiologic changes within the immune system during pregnancy typically involve an attenuation of the Th1 response and a shift toward Th2 anti-inflammatory pathways 31 , This is in the interest of protecting the developing fetus from an overactive cell-mediated immune response, while simultaneously developing antibodies for passive transfer of immunity through the placenta and breast milk.

Although there may be numerous variables at play, it seems that host survival in COVID is tied to substitution of the proinflammatory Th1 for the anti-inflammatory Th2 that is dominant in gravid hosts. In coronavirus infections, IL encourages the assembly of downstream proinflammatory cytokines that result in activation of neutrophil chemokines and secretory elements that damage lung parenchyma An investigation of polymorphisms for IL genes in SARS patients showed that individuals predisposed to lower levels of IL activation had significantly increased day survival when compared with patients prone to increased IL production Th17 lymphocytes also contribute to ARDS pathogenesis by activation of IL, which seems involved in the production of mucin and fibrin-rich secretions in patients with pulmonary edema 36 , While the role of gender in relation to Th17 function in coronavirus infections has yet to be studied, there is some literature on how this cell type affects AD.

In AD that predominantly affect males, there has been significant literature on Th17 cells playing a paramount role in disease progression 37 — For example, although multiple sclerosis MS affects 2—3 times more women than men, men tend to experience more rapid and aggressive disease progression Similarly, in systemic lupus erythematosus SLE which afflicts women 9—10 times more often than men, men tend to experience more severe complications especially nephritis leading to renal failure.

This finding suggested that male sex is a crucial and inherent element of disease-induced severity related to Th17 cells. Whether this finding is applicable to host attack in the context of SARS remains to be determined. The optimal balance of these activities is different for every pathogen, but, in the context of mouse hepatitis virus MHV coronavirus, Tregs are necessary for mild disease outcomes, as their depletion results in increased mortality 40 , While studies of Treg influences and functions have been performed on several types of respiratory viruses, there is little information on their roles against human coronaviruses.

The role and activity of Treg lymphocytes, therefore, cannot yet be verified in the context of COVID, but these cells may offer a benefit by reducing excessive damage to lung parenchyma. The transcription factor Foxp3 serves not only as a marker for Treg cells, but it is also necessary for their development, maintenance, and suppressive functions 42 , Foxp3 is encoded on the X chromosome and can escape X inactivation, giving XX females higher activity of Foxp3 and Treg cells 33 , This may give women an immunosuppressive advantage in the context of coronaviruses.

Scarcity of Treg cells from loss-of-function alterations in Foxp3 lead to severe and even lethal inflammation in human and rodent models of coronavirus infection Across several studies, there are a significant portion of COVID patients who present with lymphopenia and markers of T cell exhaustion. It was found that as patients progressed from prodromal to active symptoms, their levels of PD1 and Tim3 would directly increase.

In the same vein, patients in the ICU had much higher expression of these markers compared to non-ICU and control populations 44 , Consistent with previous work, these markers were significantly elevated in critically ill patients compared with those who were only mildly symptomatic with COVID Causes and effects of lymphopenia have not been thoroughly studied in SARS, and much less can be said for differences in sex. After an initial encounter with a pathogen, antigen-specific naive CD4 and CD8 T cells clonally expand to become effector T cells, which mount a cellular and humoral response against the offending pathogen.

After pathogen clearance, most effectors die by apoptosis, while some survive and persist to become long-lived memory T cells, and it is these cells that offer the host protection from subsequent encounters with the pathogen. Memory cells also form the basis for vaccinations which elicit a similar immune response albeit at a significantly reduced magnitude without causing disease.

Memory T cells are heterogeneous in phenotype, function and localization and include central memory Tcm , effector memory Tem , tissue resident memory Trm , terminally differentiated memory Temra , and other cells These antigen-specific cells are the basis of vaccine development, as they are skilled in triggering a targeted immune response upon re-exposure to an antigen. As SARS-CoV-2 is a novel infection, development and viability of memory T cells in men and women is truly unknown, especially in the face of viral mutation.

As SARS-CoV-2 is a novel infection, development and maintenance of memory T cells in men and women is truly unknown, especially in the face of viral mutation. Antibody secretion is the primary function of B lymphocytes. As expected, IgG antibody levels were stable while IgM antibodies reached low levels within 5 weeks and became undetectable at 7 weeks This may have to do with the upregulation of IL-4, IL, and other cytokines promoting antibody class-switching at an ultra-rapid rate These interleukins are part of the Th2 pathway which is naturally enhanced in women, suggesting that there may be a physiological sex difference in antibody switching, although no known studies have been done in this specific area 32 Another study investigated IgG levels between male and female COVID patients, stratifying patients by disease severity into mild, moderate, and severe status and into early, active, and recovery phases.

While there was no significant difference in serum IgG levels across gender in mild and recovering patients, IgG levels in women were significantly elevated in the early disease phase and in severe cases This situational increase in antibody titers cannot yet be determined as helpful or harmful in SARS, but it is worth noting for future investigation. B-cell production of cytokines make these lymphocytes powerful regulators of adaptive immunity, but in many cases turn maladaptive, such as in SARS.

A series of seven case studies was recently published on B-cell immunocompromised COVID patients and sheds light on the excessive lymphocyte immune response. Disease presentation of patients with common variable immune deficiency CVID hypogammaglobulinemia were compared to patients with agammaglobulinemia AGG.

Surprisingly, the AGG cases proved to be mild, and the patients had normal lung CT scans with no consolidation. The patients were treated in the hospital for a maximum of 3 days and went home without requiring assisted ventilation. They were in the hospital for at least two weeks and needed antiretroviral therapy ART , IL antagonists, and some required mechanical ventilation.

According to the study, the difference in patient outcomes was likely due to the lack of non-Ig B cell cytokine functions, meaning that patients with AGG avoided a host-harming cytokine storm. This cytokine activation is linked to stimulation of TLR in T-cell independent activation This process authorizes B cells to respond to activation from coronavirus-TLR7 binding by immediate expansion and differentiation without much T cell interaction.

These mature and activated B cells are capable of producing IgM as well as proinflammatory cytokines, namely IL Contrary to other immune cells discussed above , it seems that B-cell-derived cytokines may be more harmful to a female host. Women mount a stronger immune response against viral infections than men Women possess both maternal and paternal X chromosomes, which necessitates the silencing of one copy of genes in order to ensure an appropriate gene dosage.

The silencing of one copy, or X chromosome inactivation XCI , leads to functional mosaicism in women with regards to X-linked genes X chromosome inactivation is cell-specific and variable among individuals, which causes some cells to express the maternal chromosomal copy and others to express the paternal copy. In turn, this leads to a diversity of possible immune responses in females, which provides women with a wider variety of tools with which to fight pathogens Skewed inactivation patterns may additionally offer a protective effect by silencing immunodeficiency-causing mutations Furthermore, X-chromosome skewing may preferentially express beneficial alleles, leading to a larger proportion of cells producing functionally advantageous gene products X chromosome inactivation is particularly relevant to discussion of the SARS-CoV-2 immune response, as the X chromosome encodes for several genes involved in both adaptive and innate immunity, including those involved in the TLR pathway Cellular mosaicism suggests that women may be better equipped to respond to immune challenges, particularly viral infections such as SARS-CoV Evidence shows that XCI escape commonly occurs in female lymphocytes, which display atypical heterochromatic modification and tend to reactivate the inactivated X chromosome Xi The XCI escape of genes involved in the immune system may further contribute to an immunologic advantage in women.

The gene for TLR7 is located at Xp When stimulated by TLR7, biallelic B cells were 2. Increased class switching suggests that women and KS males may have enhanced humoral immune response due to TLR7 overexpression. Estrogen levels likely contribute to the sex-based difference in TLR7 signaling, as immune cells from both men and women have been shown to increase TLR7 expression post-exposure to estradiol treatment 60 , As a result, inclusion of genotypically diverse individuals may lend additional insights into the impact of XCI escape on TLR7 gene dosing.

As a result, XCI escape may be correlated with increased TLR7 signaling and more vigorous immune response to viral infections. CXorf21 is located at gene locus Xp While its exact function is presently unknown, its overexpression in female APC suggests that CXorf21 may cooperate with TLR7 to contribute to the heightened antiviral response in women The gene locus for CD40L has been identified as Xq CD40L functions in several aspects of the adaptive immune response, including T-cell differentiation, immunoglobulin class switching, and formation of long-lived plasma cells and memory B cells A comparison of antigen presenting cells APCs from TS women, KS men, and individuals with typical karyotype found that cells from typical women expressed significantly more CD40L than those from typical men or TS women Klinefelter Syndrome men yielded similar results to women possessing an XX karyotype, suggesting that XCI escape may confer an advantage against viral infections by increasing CD40L expression.

Increased CD40L in individuals with an additional chromosome may cause greater T- and B-cell activation, leading to better ability to fight off viral infection. Mannose-binding lectin was found to be depleted in patients with SARS-CoV, suggesting that the complement system may aid in the response to coronavirus infection C4, which is located at the MHC, is of particular interest because of observed differences between sexes C4 protein is more abundant in the cerebrospinal fluid and plasma of men compared to women, with a greater difference observed in men and women of childbearing age 20—50 years.

Moreover, mutation in the C4 gene affects disease risk differently in men and women. Moreover, the sex-based difference in disease incidence mirrors that of C4 protein levels and is most noticeable between men and women aged 20— As a result, the discrepancy in disease rates may be attributed to variable effects of C4 between men and women.

Human leukocyte antigen enables differentiation between host cells and pathogens through antigen presentation to the T-cell receptor TCR. As MHC binding is required for effective T-cell activity, this finding is consistent with the observation that men are biased toward infections and non-reproductive system cancers hypoactive T-cell response while women are biased toward autoimmune disorders hyperactive T-cell response.

For instance, incontinentia pigmenti, caused by mutations in NEMO, causes lethality in men but has variable presentation in women. Skewed X-inactivation favoring the wildtype allele has been observed in heterozygous women, which supports the notion that X inactivation may confer a protective advantage against immunodeficiency disorders Moreover, men with KS have been observed to escape lethality from incontinentia pigmenti FoxP3 has been mapped to locus Xp Because FoxP3 does not undergo skewed X inactivation, heterozygous women express both mutant and wildtype FoxP3 alleles equally However, women heterozygous for mutant FoxP3 exhibit normal lymphocyte levels and normal immune response to infection.

The participation of FoxP3 in positive feedback loops, in which FoxP3 protein further stimulates transcription of the FoxP3 gene, indicates that one functional copy of the gene may be sufficient to maintain appropriate levels of FoxP3 As FoxP3 is critical to Treg-mediated immunosuppression, the protective effect of mosaicism implies an immunologic advantage for women at a population level As a result, the ability to curb excessive activity by cytotoxic neutrophils, macrophages, and other immune cells may decrease risk of fatality from SARS-CoV and other coronaviruses Although Tregs may offer benefit by reducing excessive tissue damage, they may also dampen the immune system and limit ability to clear an infection, indicating the need to strike a balance between the two.

While Tregs may be less important in acute viral infections requiring an aggressive immune response, the disease characteristics for SARS-CoV-2 suggest that Tregs may play a crucial role in the antiviral response. Cellular mosaicism and the resulting improvement in genetic diversity may allow women to strike this balance more easily.

Given that women have two copies of the X chromosome, and that some of these genes may escape X-inactivation, this may help to explain the sex bias in immune responses. Additionally, it has been found that miRNA that are evolutionarily conserved are more often implicated in disease states 85 , and male-specific miRNA evolve more quickly than female miRNA 84 and therefore are less conserved.

Following the binding, the miRNA can either inhibit translation and decrease viral infectivity or it can stabilize the RNA and effectively increase translation. Together, these contribute to viral evasion of the immune response.

Sex hormones are an important biological factor contributing to the gender-bias in the immune response, and can influence outcomes of disease severity in infections and autoimmunity 4 , 88 — In general, estrogens are considered immuno-stimulatory and activate both the innate and adaptive immune responses and therefore women are able to clear pathogens more efficiently than men, whereas testosterone is immuno-suppressive, which may underlie the higher susceptibility and severity of infectious diseases in men 4.

On the other hand, the stronger immune response in women is thought to underlie the disproportionately high prevalence of AD in women over men. Sex hormones control both cellular and humoral components of the immune response and thus determine the sex-bias in susceptibility, manifestations and clinical outcomes in infections, AD and malignancies 4 , Sex hormones bind these receptors and trigger intracellular signaling cascades to regulate gene and protein expression to influence development, maturation, activation, and function of innate and adaptive immune cells during homoestasis and the immune response to infections.

Better understanding of the factors that control the immune response in a sex-specific manner is therefore crucial to not only understanding disease pathogenesis but also guiding treatment and prevention strategies and a first step toward personalized medicine. The sex-biased factors that impact immunity have developmental origins beginning in utero , infancy and childhood For example, placental hormones help shape fetal and neonatal immunity, and some of these influences are retained through adulthood.

Estrogen and progesterone are important in alveolarization and surfactant production respectively. For some infections and AD, these differences in susceptibility and severity are retained through adulthood but may change or even reverse for some allergy-related conditions and AD. Studies on the role of sex hormones in immune cells range from ex vivo cultures of human or mouse cells, or in vivo supplementation in mice after gonadectomy, including those assessing mice with genetic deletions of sex hormone receptors.

Given the wide variations in human versus rodents in vitro versus in vivo systems, epidemiological studies have shown that there is not a universal paradigm regarding the role of gender or sex hormones on the immune response to respiratory viruses. It is hypothesized that the disease outcomes are ultimately a combination of the magnitude of the immune response and degree of host tissue damage 92 , There is a male bias when a weaker immune response contributes to damage, while a female bias may occur due to a stronger immune response that causes damage.

Estrogen-ER signaling regulates innate myeloid cells including pDCs, monocytes, neutrophils, and lymphoid cells, including innate lymphoid cells ILC Estrogens contribute to delayed neutrophil apoptosis and can modulate chemotaxis and NO production in vitro. The lung-resident alveolar macrophages are important in respiratory infections and produce type I IFN for viral clearance.

These findings imply that wherein estrogen and ERa enhance while AR may dampen the type 2 responses important for lung tissue repair post-viral infections. While these cells predominantly express AR, there is tissue specific regulation by sex hormones and estrogen-ER signaling promoted uterine over lung ILC2.

Elevated numbers in IAV infections may provide superior tissue repair, however their plasticity to convert to ILC-1 like cells and IFN-g production may make them more pathogenic and contribute to immunopathology In general, estrogens are immune-stimulatory and are known to be involved in T-cell development, activation, differentiation and function 4.

Estrogen-ER signaling was shown to be necessary for normal thymic size and development, and furthermore estrogen is known to promote extrathymic T-cell differentiation in the liver. Its role in T-cell homeostasis with respect to cell survival and proliferation is complex and varies depending on cell type, context, and concentration, where physiologic doses of estradiol suppress apoptosis whereas pharmacologic doses suppress proliferation in cancer cells.

Estrogen controls cell metabolism and genes involved in metabolic activity important to stimulate T-cell differentiation and stimulate mitochondrial function. Estrogen is known to suppress IL-2 cytokine production in human T cells 94 and rat splenocytes. Accordingly, lower IL-2 levels are observed during the luteal phase of the menstrual cycle in healthy young women and thought to contribute to the observed increase in pre-menstrual infections.

CD4 T follicular helper Tfh cells are crucial for providing cognate help to B cells and promote class switching and somatic hypermutation to produce antibodies. Estrogen was shown to promote the expression of Calcineurin and CD40L in human T cells 95 , molecules important for help to B cells in the antibody response.

T cells traffic within the body to peripheral tissue sites of infection and migrate across chemokine gradients via chemokine receptors expressed on their surface. Estrogen promotes both chemokines as well as chemokine receptor expression as evidenced by ex vivo and in vivo studies in mice 4. Estrogens also enhance CD8 T-cell activity and suppress Th17 immune responses. The role of Tregs in response to viral infections is complex. Estrogen increases FoxP3 levels and Tregs in vitro and correlations have been observed in vivo.

In women with recurrent spontaneous abortions RSA , lower Treg levels were found in both follicular and luteal phases and in postmenopausal women. The suppressive capacity of these Tregs was also lower in case of RSA. Estrogen promotes B-cell homeostasis, activation, maturation, and differentiation and enhances immunoglobulin production 4.

These properties make women and female mice able to mount greater magnitudes of neutralizing antibody responses to infections and thus contribute to protection against respiratory viral infections including the SARS-CoV infections.

Estrogen administration led to increased marginal zone B cells in the spleen and in transgenic mice led to elevated anti-dsDNA antibodies. Estrogen promoted the expansion of high-affinity antibody-producing B cells and also promoted survival by increasing expression of the Bcl-2 anti-apoptotic molecule Immune cells express PR and AR, and progesterone, androgen, and testosterone in particular are considered immuno-suppressive and may counteract the effects of estrogens, contributing to the observed increased susceptibility to the SARS-CoV-2 and disease in men 98 — Androgen receptor-deficient mice exhibit reduced numbers of neutrophils and accordingly increased susceptibility of male mice to SARS-CoV infection correlated with accumulation of neutrophils in the lung.

Progesterone reduces T-cell proliferation and T-cell-dependent antibody responses in human peripheral blood and cell line or mouse studies. Its effects on B cells included reduced class switch recombination and reduced T cell dependent antibody production.

Normal testosterone levels are associated with normal respiratory capacity, whereas plasma testosterone levels decline in men with increasing age with observed associations between an increase of pro-inflammatory states and decline in testosterone in aging men.

On the other hand, high androgen levels may promote or contribute to infection because AR mediated transcription of TMPRSS2 protease which is important for viral entry into host cells. A proposed androgen sensitivity model provides a link between increased disease severity in men and the role of androgens in COVID Androgen sensitivity is primarily determined by genetic variants of the AR.

While men are generally predisposed to these effects due to higher testosterone levels compared to women, individuals with hyperandrogenism and other conditions may similarly be impacted. For example, women with hirsutism and polycystic ovarian syndrome PCOS , as well as women taking progesterone-based birth control, may be at greater risk for more severe COVID symptoms Markers of androgen sensitivity such as PCOS, androgenetic alopecia, and prostatic hyperplasia may thus be used as clinical signs of vulnerability.

In this pandemic, men are more acutely ill and exhibit higher death rates with disproportionately higher numbers in ICU and requiring ventilators compared to women. Even pregnant women had lower rates and less severe disease and complications than men. Estrogen and progesterone levels rise exponentially during pregnancy, causing a shift in the immune response, and this may underlie the observed protective effects.

The importance of these female sex hormones in the immune response to infections has triggered two clinical trials with sex hormone administration to patients with COVID Half will receive a single-use transdermal estradiol patch for 7 days, and the other half will serve as a control group and receive standard of care. The second, smaller randomized controlled trial with 40 male patients at Cedars-Sinai hospital in Los Angeles will administer progesterone in an effort to suppress the overactive immune response and mitigate immunopathology.

Inpatients with mild to moderate disease will be included and half will receive progesterone mg subcutaneous twice daily for 5 days, and the other half is a control group. Since progesterone is immune-suppressive and diminishes the proinflammatory response, this trial is intended to determine whether progesterone treatment can reduce the incidence of cytokine storm and related immunopathology leading to ARDS.

It is well-known that the commensal bacteria in the GI tract impact the immune response. Some possible mechanisms involve microbiota affecting and regulating cytokine production , while others involve microbiota modulation of the production of mucous and antiviral defensins and ROS In regard to viral infections, however, some microbiota elicit protective effects, while others serve as a route of viral entry and infection.

For example, the Lactobacillus genus prevents murine norovirus replication in vitro , and there is in vivo evidence that this genus is decreased in a mouse that is affected by norovirus. In response to Influenza and WNV, gut microbiota secrete IgA and upregulate TLR-7 in the respiratory mucosa in order to promote activation of important components of antiviral immunity—cytotoxic T lymphocytes, Th1 cells, and inflammasomes.

It is therefore possible that there is an interaction between these bacteria and the virus, though the exact relationship is unknown. One possible mechanism is that, similarly to the human norovirus, the normally commensal bacteria are harboring the virus and are producing a cytokine response that is inappropriate for the response to the infection. This ultimately would result in dysbiosis and a worse outcome for the patient. Alternatively, a relationship between ACE-2 and the gut microbiome may play a role in the immune response.

This protein is critical for the transportation of tryptophan across the epithelium, which then normally increases the production of antimicrobial peptides that affect the composition of the microbiome Lack of this peptide production would likely result in dysbiosis and an impaired immune response.

Recently, it has been noted that sex hormones have a large effect on the microbiome. Particularly, higher levels of systemic estrogen, like those seen in women, are positively associated with the richness and diversity of the fecal microbiome Additionally, germ-free female mice have higher baseline antibody levels than germ-free male mice Taken together, these studies suggest that female sex hormones, particularly estrogen, have a pro-inflammatory effect 4 that promotes a more robust response to infection.

In addition to lacking the stimulatory effects of estrogen, men also produce androgens that seem to have a protective mechanism against the immune response. Furthermore, the testosterone surge at puberty in male mice dampens B- and T-cell development Commensal bacteria in the gastrointestinal tract have a role in regulation of testosterone levels An in vivo study found that the number of species in microbiomes of mice was not significantly different during the pre-pubescent stage but was significantly different following puberty This suggests that hormone changes during puberty drive changes in the microbiome.

Further, the microbiome elevates androgens to a level that confers protection from type 1 diabetes in mice , , which illustrates the synergistic effect of the male hormones and the microbiome. While this is thought to be a major factor in the protection against autoimmunity, it is also reasonable to think that the immune response may be dampened below the level that is needed for a strong response to pathogens.

Overall, these findings suggest that the microbiome is an important biological factor in the sex-bias in response to infection and may be involved in the SARS-CoV-2 responses. This binding leads to the subsequent downregulation of ACE2, which is considered to be protective against lung injury. Stimulation of AGTR1a receptor by angiotensin II leads to endothelial cell permeability which may explain the increase in pulmonary pathology with decreasing levels of expressed ACE2.

The location of ACE2 on the X chromosome suggests possible genetic influence in the elevated male mortality rate. For example, mutations in ACE2 in one cell line may alter the catalytic site and lead to divergent viral susceptibilities between cell populations decreasing peak viral load Substitutions in these amino acids, among other mutations, may alter binding affinity between the RBD and receptor, limiting the ability of the virus to enter the cell and propagate.

Variable expression of ACE2 may also influence patient outcomes. Viral entry into a cell causes downregulation of ACE2, which may be detrimental in patients already deficient in ACE2 ACE2 downregulation leads to pulmonary edema, alveolus hyalinization, and leukocyte accumulation.

Cecal ligation and perforation of ACE2 knockout mice has also been shown to increase lung failure and tissue damage, indicating that ACE2 may confer a protective role in microbial infection Gene dosage, however, likely does not contribute to the sex-based difference in SARS-CoV-2 response, as evidence suggests that sexual dimorphism in ACE2 expression persists in renal tissue but not cardiac or pulmonary tissue under non-pathological conditions Moreover, changes in chromosome dosage was not observed to affect ACE2 expression in mice that had undergone gonadorectomy.

This finding implies possible hormonal but not chromosomal effects in ACE2 expression levels. Despite limited evidence supporting the effect of chromosome dosage in the increased male mortality rate, cellular mosaicism in women may offer protection against immune deficiency.

As a result, the effect of detrimental mutations to ACE2 may be more pronounced in men than women, altering the clinical course in male versus female patient populations. The ACE2 receptor is expressed in the type II pneumocytes of the lungs and also in other tissues, including the heart, tubular epithelial cells in kidneys, testis, adipose tissue, and the enterocytes in the gastrointestinal tract and vascular endothelial cells A recent study evaluated ACE2 expression in older men and women with heart failure and found in two independent cohorts that circulating plasma concentrations of ACE2 were higher in men than in women This may reflect differences in tissues from men versus women.

Two studies utilized systems biology approaches of meta-analysis, co-expression and network analysis to draw information on the expression, regulation and gender bias of ACE2 receptor expression. The highest levels of ACE2 expression were found in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, medium levels in the lungs, colon, liver, bladder, and adrenal gland, and lowest in blood, spleen, bone marrow, brain, blood vessels, and muscle.

While they did not find a significant difference in gene expression between men and women, ACE2 expression in the lungs was positively correlated with immune signatures in men and negatively in women. In addition the HPA database showed high levels of both ACE2 gene and protein in the gastrointestinal tract duodenum, small intestine, colon, and rectum , kidney, gallbladder, and male tissues testis and seminal vesicle.

Taken together these data suggest that the differential host immune responses may underlie the gender-bias of the remarkably distinct clinical outcomes. The other study of patients with severe COVID who had comorbidities evaluated data from over lung transcriptome samples and found that ACE2 was highly expressed in these patients, compared to controls. Suggesting epigenetic regulation of ACE2 in the human lung. ACE2 is known to be expressed in Leydig cells of both mice and humans, albeit testosterone-independent, and is thought to contribute to steroid synthesis , It is also expressed in ovarian granulosa cells and its levels increase in correlation with increasing LH levels.

In addition to expression in the gonads, ACE2 expression and activity is influenced by sex hormones in adipose tissue, myocardium, and kidneys.

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Progesterone reduces T-cell proliferation and T-cell-dependent antibody responses in human peripheral blood and cell line or mouse studies. Its effects on B cells included reduced class switch recombination and reduced T cell dependent antibody production. Normal testosterone levels are associated with normal respiratory capacity, whereas plasma testosterone levels decline in men with increasing age with observed associations between an increase of pro-inflammatory states and decline in testosterone in aging men.

On the other hand, high androgen levels may promote or contribute to infection because AR mediated transcription of TMPRSS2 protease which is important for viral entry into host cells. A proposed androgen sensitivity model provides a link between increased disease severity in men and the role of androgens in COVID Androgen sensitivity is primarily determined by genetic variants of the AR.

While men are generally predisposed to these effects due to higher testosterone levels compared to women, individuals with hyperandrogenism and other conditions may similarly be impacted. For example, women with hirsutism and polycystic ovarian syndrome PCOS , as well as women taking progesterone-based birth control, may be at greater risk for more severe COVID symptoms Markers of androgen sensitivity such as PCOS, androgenetic alopecia, and prostatic hyperplasia may thus be used as clinical signs of vulnerability.

In this pandemic, men are more acutely ill and exhibit higher death rates with disproportionately higher numbers in ICU and requiring ventilators compared to women. Even pregnant women had lower rates and less severe disease and complications than men. Estrogen and progesterone levels rise exponentially during pregnancy, causing a shift in the immune response, and this may underlie the observed protective effects.

The importance of these female sex hormones in the immune response to infections has triggered two clinical trials with sex hormone administration to patients with COVID Half will receive a single-use transdermal estradiol patch for 7 days, and the other half will serve as a control group and receive standard of care. The second, smaller randomized controlled trial with 40 male patients at Cedars-Sinai hospital in Los Angeles will administer progesterone in an effort to suppress the overactive immune response and mitigate immunopathology.

Inpatients with mild to moderate disease will be included and half will receive progesterone mg subcutaneous twice daily for 5 days, and the other half is a control group. Since progesterone is immune-suppressive and diminishes the proinflammatory response, this trial is intended to determine whether progesterone treatment can reduce the incidence of cytokine storm and related immunopathology leading to ARDS. It is well-known that the commensal bacteria in the GI tract impact the immune response.

Some possible mechanisms involve microbiota affecting and regulating cytokine production , while others involve microbiota modulation of the production of mucous and antiviral defensins and ROS In regard to viral infections, however, some microbiota elicit protective effects, while others serve as a route of viral entry and infection.

For example, the Lactobacillus genus prevents murine norovirus replication in vitro , and there is in vivo evidence that this genus is decreased in a mouse that is affected by norovirus. In response to Influenza and WNV, gut microbiota secrete IgA and upregulate TLR-7 in the respiratory mucosa in order to promote activation of important components of antiviral immunity—cytotoxic T lymphocytes, Th1 cells, and inflammasomes.

It is therefore possible that there is an interaction between these bacteria and the virus, though the exact relationship is unknown. One possible mechanism is that, similarly to the human norovirus, the normally commensal bacteria are harboring the virus and are producing a cytokine response that is inappropriate for the response to the infection. This ultimately would result in dysbiosis and a worse outcome for the patient.

Alternatively, a relationship between ACE-2 and the gut microbiome may play a role in the immune response. This protein is critical for the transportation of tryptophan across the epithelium, which then normally increases the production of antimicrobial peptides that affect the composition of the microbiome Lack of this peptide production would likely result in dysbiosis and an impaired immune response.

Recently, it has been noted that sex hormones have a large effect on the microbiome. Particularly, higher levels of systemic estrogen, like those seen in women, are positively associated with the richness and diversity of the fecal microbiome Additionally, germ-free female mice have higher baseline antibody levels than germ-free male mice Taken together, these studies suggest that female sex hormones, particularly estrogen, have a pro-inflammatory effect 4 that promotes a more robust response to infection.

In addition to lacking the stimulatory effects of estrogen, men also produce androgens that seem to have a protective mechanism against the immune response. Furthermore, the testosterone surge at puberty in male mice dampens B- and T-cell development Commensal bacteria in the gastrointestinal tract have a role in regulation of testosterone levels An in vivo study found that the number of species in microbiomes of mice was not significantly different during the pre-pubescent stage but was significantly different following puberty This suggests that hormone changes during puberty drive changes in the microbiome.

Further, the microbiome elevates androgens to a level that confers protection from type 1 diabetes in mice , , which illustrates the synergistic effect of the male hormones and the microbiome. While this is thought to be a major factor in the protection against autoimmunity, it is also reasonable to think that the immune response may be dampened below the level that is needed for a strong response to pathogens. Overall, these findings suggest that the microbiome is an important biological factor in the sex-bias in response to infection and may be involved in the SARS-CoV-2 responses.

This binding leads to the subsequent downregulation of ACE2, which is considered to be protective against lung injury. Stimulation of AGTR1a receptor by angiotensin II leads to endothelial cell permeability which may explain the increase in pulmonary pathology with decreasing levels of expressed ACE2. The location of ACE2 on the X chromosome suggests possible genetic influence in the elevated male mortality rate. For example, mutations in ACE2 in one cell line may alter the catalytic site and lead to divergent viral susceptibilities between cell populations decreasing peak viral load Substitutions in these amino acids, among other mutations, may alter binding affinity between the RBD and receptor, limiting the ability of the virus to enter the cell and propagate.

Variable expression of ACE2 may also influence patient outcomes. Viral entry into a cell causes downregulation of ACE2, which may be detrimental in patients already deficient in ACE2 ACE2 downregulation leads to pulmonary edema, alveolus hyalinization, and leukocyte accumulation.

Cecal ligation and perforation of ACE2 knockout mice has also been shown to increase lung failure and tissue damage, indicating that ACE2 may confer a protective role in microbial infection Gene dosage, however, likely does not contribute to the sex-based difference in SARS-CoV-2 response, as evidence suggests that sexual dimorphism in ACE2 expression persists in renal tissue but not cardiac or pulmonary tissue under non-pathological conditions Moreover, changes in chromosome dosage was not observed to affect ACE2 expression in mice that had undergone gonadorectomy.

This finding implies possible hormonal but not chromosomal effects in ACE2 expression levels. Despite limited evidence supporting the effect of chromosome dosage in the increased male mortality rate, cellular mosaicism in women may offer protection against immune deficiency.

As a result, the effect of detrimental mutations to ACE2 may be more pronounced in men than women, altering the clinical course in male versus female patient populations. The ACE2 receptor is expressed in the type II pneumocytes of the lungs and also in other tissues, including the heart, tubular epithelial cells in kidneys, testis, adipose tissue, and the enterocytes in the gastrointestinal tract and vascular endothelial cells A recent study evaluated ACE2 expression in older men and women with heart failure and found in two independent cohorts that circulating plasma concentrations of ACE2 were higher in men than in women This may reflect differences in tissues from men versus women.

Two studies utilized systems biology approaches of meta-analysis, co-expression and network analysis to draw information on the expression, regulation and gender bias of ACE2 receptor expression. The highest levels of ACE2 expression were found in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, medium levels in the lungs, colon, liver, bladder, and adrenal gland, and lowest in blood, spleen, bone marrow, brain, blood vessels, and muscle.

While they did not find a significant difference in gene expression between men and women, ACE2 expression in the lungs was positively correlated with immune signatures in men and negatively in women. In addition the HPA database showed high levels of both ACE2 gene and protein in the gastrointestinal tract duodenum, small intestine, colon, and rectum , kidney, gallbladder, and male tissues testis and seminal vesicle. Taken together these data suggest that the differential host immune responses may underlie the gender-bias of the remarkably distinct clinical outcomes.

The other study of patients with severe COVID who had comorbidities evaluated data from over lung transcriptome samples and found that ACE2 was highly expressed in these patients, compared to controls. Suggesting epigenetic regulation of ACE2 in the human lung. ACE2 is known to be expressed in Leydig cells of both mice and humans, albeit testosterone-independent, and is thought to contribute to steroid synthesis , It is also expressed in ovarian granulosa cells and its levels increase in correlation with increasing LH levels.

In addition to expression in the gonads, ACE2 expression and activity is influenced by sex hormones in adipose tissue, myocardium, and kidneys. Higher ACE and ACE2 activity and cardiac hypertrophy was found in male rats compared to female rats which was reduced after orchiectomy, while ovariectomy elevated ACE2 and hypertrophy in females In female mice, HFD increased adipose tissue ACE2 which was reversed by ovariectomy implying that estrogen increases ACE2 expression and activity in adipose tissue and kidneys.

Importantly, ovariectomy or treatment with an ER antagonist in SARS-CoV infected female mice increased the mortality rate therefore, suggesting a protective effect for the ER signaling pathway in mice 3. While sex hormones influence ACE2 expression and activity to influence outcomes in obesity, hypertension, and related comorbidities, thus influencing COVID outcomes, the effect of COVID on male sex hormones has been recently explored.

Given that the ACE2 receptor is expressed in the testes, a study from Hubei province of China reports that the COVID impacts male gonadal function and observed alterations in hormone levels. They studied 81 men with COVID and found that serum luteinizing hormone LH levels were increased while the ratio of testosterone to LH and the ratio of follicle stimulating hormone FSH to LH were significantly lower compared with age-matched healthy men Recent reports of increased frequency of venous thromboembolism, associated with worse outcomes in patients with COVID warrant caution in treatment with testosterone, specifically in hypogonadal men with greater genetic predisposition.

Besides its role in infection immunity, sex is equally important in the immune response to vaccines , Women not only mount stronger antibody and T-cell responses to vaccinations than men, but also suffer more adverse events. Yet there is a serious lack of attention to gender in vaccine trials.

This leads to inappropriate dosage of vaccines as evidenced by the fact that the same magnitude of protective immunity is achieved by half the dose of seasonal influenza vaccine in women compared to men.

Likewise, these gender-blind vaccination strategies lead to increased adverse effects in women. Increased hospitalizations and mortality have been observed in female infants and girls following DPT, measles and oral polio vaccinations Sex-based biological factors include differences across the immune system within innate immunity, antibody responses and T cell responses.

Genetics, sex hormones, epigenetic factors, nutrition, and the microbiome are important biological contributors to these sex-based differences. Vaccine-related research and clinical trials, including those currently underway for COVID, must thus include sex as a key variable when measuring and reporting outcomes of immunogenicity and reactogenicity. This information would help tailor vaccine dosage and strategies appropriately to maximize protective immunity while minimizing adverse effects.

The COVID pandemic has revealed a striking gender-bias with increased case and mortality rates in men compared with women across the lifespan. Besides behavioral and lifestyle factors, sex-based physiological differences influence the host immune response to infections.

Sex chromosome linked genes, sex hormones, and the microbiome control aspects of the innate and adaptive immune responses to infection. Better understanding of these factors is necessary to tailor therapies and vaccine strategies in a step toward sex-based personalized medicine. VM conceptualized the article. All authors contributed to the literature review, writing, and finalizing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Dr. Robert Shmerling for critical review of the manuscript and helpful suggestions. COVID infection: the perspectives on immune responses. Cell Death Differ. Clinical characteristics of coronavirus disease in China. New Engl J Med. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection.

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Cell Mol Immunol. The effect of sex on immune cells in healthy aging: elderly women have more robust natural killer NK lymphocytes than do elderly men. Google Scholar. Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors. Int Immunopharmacol. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. Am J Obstet Gynecol.

Natl Sci Rev. Klein SL. Immune cells have sex and so should journal articles. Ellington S. Characteristics of women of reproductive age with laboratory-confirmed sars-cov-2 infection by pregnancy status — United States, January 22—June 7, Wu D, Yang XO. J Microbiol Immunol Infect. Voskuhl R. Sex differences in autoimmune diseases. Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis.

Scand J Immunol. Role of regulatory T cells in coronavirus-induced acute encephalitis. Control of regulatory T cell development by the transcription factor foxp3. Nat Immunol. Moon C. Bekeredjian-Ding I, Jego G. Toll-like receptors—sentries in the B-cell response. Lesson from patients with agammaglobulinemia. T cell-mediated immune response to respiratory coronaviruses. Immunol Res. Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.

J Virol. Clin Immunol. Genes Immun. Nat Med. J Med Virol. The X chromosome and sex-specific effects in infectious disease susceptibility. Human Genomics. Chamekh M, Casimir G. Editorial: sexual dimorphism of the immune inflammatory response in infectious and non-infectious diseases. Spolarics Z. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection.

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Cutting Edge: CXCR3 escapes X chromosome inactivation in t cells during infection: potential implications for sex differences in immune responses. Gender differences of B cell signature in healthy subjects underlie disparities in incidence and course of SLE related to estrogen.

J Immunol Res. Plasmid DNA encoding IFN-gamma-inducible protein 10 redirects antigen-specific T cell polarization and suppresses experimental autoimmune encephalomyelitis. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. Lysosomal pH is regulated in a sex dependent manner in immune cells expressing CXorf Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus.

Nat Commun. Immunol Rev. A critical role for Cd40—Cd40 ligand interactions in amplification of the mucosal Cd8 T cell response. J Exp Med. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis. Sex bias in MHC I-associated shaping of the adaptive immune system. J Biol Chem. Acta Biochim Biophys Sin Shanghai. Sun BK, Tsao H.

X-Chromosome inactivation and skin disease. J Investigat Dermatol. A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum Genet. Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation.

Mercer F, Unutmaz D. The biology of FoxP3: a key player in immune suppression during infections, autoimmune diseases and cancer. Adv Exp Med Biol. The regulation of immune tolerance by FOXP3. Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it?

Dandekar AA, Perlman S. Immunopathogenesis of coronavirus infections: implications for SARS. Identification and analysis of human sex-biased MicroRNAs. Genom Proteom Bioinform. An analysis of human MicroRNA and disease associations. PLoS One. Physiol Genomics. The role of microRNAs in respiratory viral infection: friend or foe? Rev Med Virol. SeXX matters in immunity.

Trends Immunol. Sex differences in immune responses. Lotter H, Altfeld M. Sex differences in immunity. Developmental origin and sex-specific risk for infections and immune diseases later in life. PLoS Pathogens e Sex and sex steroids impact influenza pathogenesis across the life course.

Mol Med. Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. J Rheumatol. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Panchanathan R, Choubey D. Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity. Mol Immunol. Pozzilli P, Lenzi A.

Metab Clin Exp. Androgen-induced immunosuppression. Hormonal modulation of the immune system—A spotlight on the role of progestogens. Autoimmun Rev. Drug Dev Res. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response.

Linking the human gut microbiome to inflammatory cytokine production capacity. Microbiota and its role on viral evasion: is it with us or against us? Front Cell Infect Microbiol. Pang IK, Iwasaki A. Control of antiviral immunity by pattern recognition and the microbiome. ACS Nano. Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition.

Microbes Infect. Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med. The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility. The impact of gut microbiota on gender-specific differences in immunity.

Welcome to the microgenderome. Gender bias in autoimmunity is influenced by microbiota. Eur J Intern Med. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV a double-edged sword? Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin—angiotensin—aldosterone inhibitors.

Eur Heart J. Infect Dis Poverty. Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. Arterioscl Thrombos Vascul Biol. Sex differences in the metabolic effects of the renin-angiotensin system. Biol Sex Differen. Harper A, Flanagan KL. Effect of sex on vaccination outcomes: important but frequently overlooked. Curr Opin Pharmacol. Sex differences in vaccine-induced humoral immunity. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Moulton, vmoulton bidmc. Wu 1,2 , Allison P. Spihlman 1,2 and Vaishali R. Introduction Infecting both wild animals and royalty, the novel coronavirus has been able to proliferate and cause the worst pandemic of the 21st century. The majority of studies addressing the functional impact of T cell responses against respiratory virus infections come from mice infected with a variety of natural and mouse-adapted pathogens.

Zhao et al. An elegant study analyzed the immune compartments in the pulmonary areas and the geographical relevance of T lymphocytes in the lung airway, parenchyma versus vasculature during a challenge with SARS-CoV in mice. Epitope mapping study indicated that a cluster of overlapping peptides located in the C-terminal region amino acids [aa] to of N protein contained at least two different T-cell epitopes. The clinical significance of T cell responses to other harmful viruses has been discussed in the context of survivors to previous pandemics.

Genetic defects in type 1 IFN signaling were associated with severe outcome. Zaire ebolavirus EBOV is a negative sense single-stranded RNA virus and the etiologic agent of the highly lethal Ebola virus disease outbreak, which caused 8, deaths in West Africa.

Knowledge on EBOV has been limited by the biosafety level 4 degree of containment required to study the viral particles and patient samples. Fatal cases were characterized by a high degree of immunosuppression. In a recent high dimensional flow cytometry study, three distinct immunotypes were identified by analyzing patients hospitalized for COVID compared to convalescent and healthy individuals: i.

The spike protein is a homotrimer. Each protomer is composed by two subunits S1 and S2. The receptor binding domain RBD , which is part of the S1 subunit, binds to ACE2, triggers a conformational change in the receptor and then facilitates membrane fusion. Nonetheless, a recent epidemiological study did not support this hypothesis.

In line with another study conducted in SARS survivors, this work suggests that this epitope is likely to be useful as an immunogen in human populations. The T cell response plays a critical role in orchestrating the antiviral response since a close relationship between TCR diversity and the immune response to viral antigen has been reported. T FH cells follicular helper T cells are essential for antibody-mediated humoral immunity against various pathogens in rodents.

After viral infection, T FH cells facilitate the generation of long-lived memory B cells and plasma cells that produce virus specific neutralizing antibodies. There is a need to study this T FH cell subset in the blood of patients diagnosed with COVID at different kinetics of the ongoing immune response, since peripheral T FH can be followed in the blood. The quality of the Ig production makes a difference for the long-term immunization against harmful viruses. Antibodies undergo an intricate process of adaptation to the viral antigens i.

In a Darwinian-like manner, B cells harboring somatic mutations that increase affinity for the antigen give more progeny with an enrichment in high affinity somatic variants across the subjects. The extent to which affinity maturation is required for the generation of protective and neutralizing antibodies varies from virus to virus.

The natural serologic response to EBOV infection has been well-characterized, with specific IgM responses generally occurring 10—29 d after symptom onset in most patients. While for influenza virus, low affinity antibodies emerging early after infection can be protective, EBOV infection generates highly protective neutralizing antibodies late after 1 year in survivors, once EBOV-specific B cell lineages have acquired substantial somatic mutations, although potent antibody responses monitored at earlier phases that may not necessitate mutations may confer some protection albeit directed toward different epitopes cleaved-as opposed to naive- surface glycoprotein found at late time points.

The N protein is conserved among different coronaviruses and induces cross-reacting antibodies. All patients showed detectable neutralizing antibodies. There was no obvious correlation between the time of seroconversion and abrupt virus elimination.

This may be explained by the glycosylation pattern of the viral surface proteins that may attenuate the neutralization potential of the antibody response, as described in the case of EBOV infection. Rather, seroconversion early in week 2 coincided with a slow but steady decline of sputum viral load. The use of a reliable serologic test is necessary in clinical practice to detect asymptomatic COVID cases that have healed on their own, to estimate the seroprevalence of the disease in the general population, and to identify the presence of a serologic response as protective against SARS- CoV-2 reinfection.

Seroconversion begins on the sixth day after the onset of symptoms and peaks in the second week, as usually reported for viral infections. In a macaque model, Liu et al. Technical progress is being made to circumvent this cross-reactivity. No signal was detected for IgG4 and reagents for IgG2 were unavailable. In a recent study, Robbiani et al. NCT , and anecdotal evidence from the epidemic in Wuhan suggests that compassionate use of these interventions was successful.

Three patients were discharged from the hospital in good medical conditions on the first day post- transfusion. Seven days after the transfusion, increased levels of neutralizing antibodies were observed while viral load became undetectable. Preclinical studies in rodents tested a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene into replication-competent vesicular stomatitis virus VSV -based vaccine.

In human, a recombinant adenovirus type-5 vectored COVID vaccine was tested in an open label, non randomized, first human trial. Preliminary results showed the detection neutralizing activity in all participants after the second dose vaccination. Likewise, a wide range of vaccine candidates have been developed against these coronaviruses, including subunit, whole inactivated virus, DNA, and vectored vaccines.

In contrast, live-attenuated vaccines have a long history of success. Attenuation of viruses generally relies on the previous identification of genes involved in viral virulence in specific hosts, often encoding proteins that antagonize the innate immune response. Their deletion leads to viruses that are attenuated in their virulence and, therefore, may be developed into candidate vaccines. The development of antibodies protecting during Sars CoV-2 infection is an urgent public health and vaccine development issue.

The S1b domain of this protein commonly binds the human angiotensin converting enzyme 2 ACE2. Dogan et al. Balancing immune-mediated virus clearance and overt immunopathology may be difficult in certain patients. In contrast to exacerbated T cell activation, T cell exhaustion could represent the cause of this inflammatory syndrome.

Mechanisms leading to peripheral lymphopenia and severe disease remain unclear. Three non-exclusive hypotheses have been emitted. First SARS-CoV-2 might directly infect and the destroy splenic and lymph nodes follicles, as indicated by the post mortem analysis of 6 patients.

Furthermore, the increased incidence of Kawasaki disease in young children with COVID infections, even in the absence of cardiovascular predisposition, is indicative of SARS- CoV-2 vascular tropism and vascular damage. Hence, pulmonary complications result in part from endothelitis, activation of coagulation and myeloid pathways, maybe calling for therapeutics targeting angiopoietin-2, bevacizumab, a monoclonal antibody that binds VEGF and counteracts its vessel permeabilizing effect.

Recent studies revealed that emergency myelopoiesis marked by the occurrence of pre-neutrophils and immature neutrophils is correlated with the severity of the disease. In mouse models in which coronavirus replication is increased by genetic defects in innate lines of defense such as TRIF, TLR3, TLR4, C3, NLRP3 deficiencies , increased weight loss and fatality are associated with excess recruitment of neutrophils and monocytic cells to the lung, correlating with acute respiratory distress syndrome.

Neutrophils facilitate trapping and killing of pathogens through an organized cell death pathway in which decondensed chromatin and antimicrobial proteins are expelled from the cell to form Neutrophils Extracellular Traps NETs. The first anecdotic report identified a favourable course of treatment with tocilizumab TCZ , while the first cohort study reported that 3 of the 10 treated patients died perhaps because TCZ was used in combination with methylprednisolone.

This is the first cohort study reporting strong promising results. In addition, progression to secondary haemophagocytic lymphohistiocytosis was reported for severe COVID patients presenting a cytokine release syndrome under tocilizumab treatment. While it appears clear that T lymphocyte responses can confer effective and durable protection against SARS-CoV-2, the role of humoral responses is still elusive.

Paradoxically, the mortality rate associated with COVID19 is mainly the result of a dysregulated immunopathology in response to the virus rather than organ injury due to the viral replication itself. There is an urgent need for a high dimensional and longitudinal follow-up of the underlying immunological mechanisms across the different stages of the COVID to make more rational and personalized therapeutic decision.

Consortia aimed at patient stratification and appropriate clinical management are being constituted to bring together the required expertise to reach this goal in short term. Importantly, pilot and large clinical trials based on antivirals, immunostimulatory and immunosuppressive drugs are being conducted for early and late stages of COVID in hospitals of these consortia, awaiting diagnostic tools to optimally stratify patients according to their risk. The race between viral replication and the elicitation of a productive and coordinated immune response likely necessitates drugs that operate on those sides likely as a result of off-target effects or combinatorial regimen.

Medium-term goals include the development of effective vaccines against highly pathogenic CoVs. National Center for Biotechnology Information , U. Journal List Oncoimmunology v. Published online Aug Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. In the second phase of the disease, abnormal blood parameters involved in the severity of the disease can be observed.

Then,from day 9 to 12 after the onset of symptoms phase III , sudden deterioration caused by the cytokine storm syndrome and pulmonary macro and micro embolism can lead to acute respiratory distress syndrome phase IV and death. Therapeutic strategies have been proposed for each stage of the disease. Oxygen and intensive care therapy are used in the third and fourth phases of the disease. Figure 2. Extrapulmonary manifestations are observed in one quarter to one third of hospitalized patients.

Four mechanisms are involved in the pathophysiology of multiorgan injury: i. Dysregulation of the renin-angiotensin-aldosterone system RAAS. Endothelial cell damage and thrombo-inflammation and iv. Dysregulation of the immune system and cytokine release syndrome that causes disseminated organ injuries.

Histopathological analyses identified the virus in the lung, the kidney, the myocardium, the brain, and the gastro-intestinal tissues. Innate barriers to viral infection paving the way to T and B cell responses Lung parenchyma local immunity The lung is a complex organ with specialized structures to allow for adequate gas exchange. Figure 3.

Putative immune scenarios associated with protective immune responses. Bone marrow-derived monocytes and DC precursors migrate to lung and inflammatory lesions to cross-present apoptotic virally-infected epithelial cells. Bats are increasingly recognized as the natural reservoirs of viruses of public health concern. Furthermore, the unexpected high number of T cells in bats BM could suggest a role for this primary lymphoid organ in T celldevelopment. Relevant TLR signaling pathways TLR agonists and antagonists have been discussed as potential compounds with broad-spectrum therapeutic bioactivity against a number of respiratory infections in the context of antivirals and vaccine adjuvants.

T cell response against coronaviruses The significance of T cell responses to respiratory coronaviruses has been extensively reviewed. Theoretical principles A and tentative scheme B of the kinetics of virus replication and infectivity, humoral and cellular immune responses, based on previous human pandemic infections with betacoronaviruses.

T FH cells follicular helper T cells T FH cells follicular helper T cells are essential for antibody-mediated humoral immunity against various pathogens in rodents. The humoral response against coronaviruses The quality of the Ig production makes a difference for the long-term immunization against harmful viruses. Serological cross -reactivity and neutralizing antibodies The SARS-Cov2 nucleocapsid and S genes share some degrees of sequence homology with other human coronaviruses. Vaccination Preclinical studies in rodents tested a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene into replication-competent vesicular stomatitis virus VSV -based vaccine.

Monoclonal antibodies The development of antibodies protecting during Sars CoV-2 infection is an urgent public health and vaccine development issue. The wrong side of the janus face: virus-induced immunopathology Balancing immune-mediated virus clearance and overt immunopathology may be difficult in certain patients.

Immature neutrophils and the cytokine storm Recent studies revealed that emergency myelopoiesis marked by the occurrence of pre-neutrophils and immature neutrophils is correlated with the severity of the disease. Competing interests statement LZ, RD and GK are cofounders of EverImmune, a biotech company devoted to the use of commensal microbes for the treatment of cancers.

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