Sex Differences In Immune Responses Research Articles

Sex differences in CD8+ T cell responses during adaptive immunity.

Biological sex is an important variable that influences the immune system's susceptibility to infectious and non-infectious diseases and their outcomes. Sex dimorphic features in innate and adaptive immune cells and their activities may help to explain sex differences in immune responses. T lymphocytes in the adaptive immune system are essential to providing protection against infectious and chronic inflammatory diseases. In this review, T cell responses are discussed with focus on the current knowledge of biological sex differences in CD8+ T cell mediated adaptive immune responses in infectious and chronic inflammatory diseases. Future directions aimed at investigating the molecular and cellular mechanisms underlying sex differences in diverse T cell responses will continue to underscore the significance of understanding sex differences in protective immunity at the cellular level, to induce appropriate T cell-based immune responses in infection, autoimmunity, and cancer. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.

A viral-specific CD4+ T cell response protects female mice from Coxsackievirus B3 infection.

Biological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality. We inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection. We found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model. Overall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.

Mechanisms and consequences of sex differences in immune responses.

Biological sex differences refer to differences between males and females caused by the sex chromosome complement (that is, XY or XX), reproductive tissues (that is, the presence of testes or ovaries), and concentrations of sex steroids (that is, testosterone or oestrogens and progesterone). Although these sex differences are binary for most human individuals and mice, transgender individuals receiving hormone therapy, individuals with genetic syndromes (for example, Klinefelter and Turner syndromes) and people with disorders of sexual development reflect the diversity in sex-based biology. The broad distribution of sex steroid hormone receptors across diverse cell types and the differential expression of X-linked and autosomal genes means that sex is a biological variable that can affect the function of all physiological systems, including the immune system. Sex differences in immune cell function and immune responses to foreign and selfantigens affect the development and outcome of diverse diseases and immune responses.

TMIC-02. SEX DIFFERENCES IN IMMUNE RESPONSE IN A MURINE GLIOBLASTOMA RESECTION MODEL CONFER A FEMALE SURVIVAL ADVANTAGE

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of 15-20 months, despite standard of care treatment, which includes surgical resection, radiation, and chemotherapy. GBM is 1.6 times more common in males and overall survival can be up to 10 months shorter in males. Females are more responsive to standard of care therapy, but the mechanism behind these differences is not clear. The immune system is known to be suppressed in GBM patients, and recent studies have found sex differences in immune response. While pre-clinical GBM models are used to interrogate pathophysiology and response to therapeutic interventions, few of these models include surgical resection, despite its role in the standard of care for patients and as a defining therapy in prolonging survival. We developed a pre-clinical GBM resection model to evaluate whether there is a sex bias in survival and to interrogate sex-specific immune changes after surgery. We found that C57BL/6 mice implanted with syngeneic GBM cells demonstrate a sex bias after surgical resection, with males surviving for a median of 24 days compared to 33 days for females. To understand how the immune response is affected by surgical resection in males and females with GBM, we performed flow cytometry to characterize the immune phenotype and found that female mice who underwent resection of their tumors had significantly higher levels of CD4+ T cells in their resection cavity than male mice who underwent resection. The immune phenotype will be further characterized over time to evaluate how it evolves in each sex. These data support prior observations that the mechanisms of immunosuppression are different in males and females. They further underscore the complexity of sex bias in GBM and the need to account for surgical resection and sex in pre-clinical models to investigate next-generation therapeutic strategies.

Sex differences in neurologic presentation and outcome of SARS-CoV-2, especially cerebrovascular manifestations

Neurological manifestations of COVID-19 and their impact have not been well characterized. Neurological involvement may be caused directly by the effects of the virus infecting the brain or indirectly by the local and systemic immune responses against the virus. Acute cerebrovascular disease, particularly ischemic stroke, has emerged as a serious complication of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The arrival of COVID-19 represented a unique occasion to study sex difference, and accentuated the need for further study to elucidate the mechanisms that differentiate clinical outcomes among male and female patients. Recent pandemics has a clear sex disparity in clinical outcomes, and morbidity and mortality from COVID-19 are higher among men. Interestingly, the previous decade, there was sparse literature evaluating the impact of sex differences on outcomes in infectious diseases, especially on neurologic complications. Ongoing advances in scientific research have demonstrated sex differences in the neurological complications of neuroinfectious diseases, and sex and disparities in health care are frequently encountered. The evidence for potential sex differences and gender inequalities, including socioeconomic status and occupational exposure in the COVID-19 pandemic is continuing to emerge. In summary, sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic. Morbidity and mortality from COVID-19 are greater for males, however, the mechanisms for this difference are unclear. Understanding the differences in outcomes between males and females improve the effectiveness of health interventions. However, outcomes of the neurologic complications of infectious disease may be partially explained by sex differences in immune responses. With this narrative, we intend to provide the reader with a comprehensive coverage of where we currently stand regarding sex differences specific, especially on outcomes critical neurologic manifestations of the SARS-CoV-2 infection.

Effects of pair-housing pubertal and adult male and female mice on LPS-induced age-dependent immune responses: A potential role for the gut microbiota

Puberty is a critical period of development that is marked by the maturation of the stress and immune systems. There are marked age and sex differences in peripheral and central inflammatory responses to an immune challenge between pubertal and adult mice. Given the strong link between the gut microbiome and immune system, it is possible that the age and sex differences in immune responses are mediated by age and sex differences in gut microbial composition. The current study investigated whether cohousing adult and pubertal CD1 mice through three weeks of pair-housing, with the potential for microbiome exchange via coprophagy and other close contact, could mitigate age-dependent immune responses. Cytokine concentrations in the blood and cytokine mRNA expression in the brain were assessed following exposure to the immune challenge lipopolysaccharide (LPS). The results show that all mice displayed increased cytokine concentrations in serum and central cytokine mRNA expression in the hippocampus, hypothalamus and prefrontal cortex (PFC) at eight hours following LPS treatment. Pubertal male and female mice, that were pair-housed with a pubertal counterpart, displayed lower cytokine concentrations in serum and lower cytokine mRNA expression in the brain compared to adult mice that were pair-housed with an adult counterpart. However, when adult and pubertal mice were pair-housed, the age differences in both peripheral cytokine concentrations and central cytokine mRNA expression were mitigated. We also found that pair-housing adult and pubertal mice eliminated the age difference in gut bacterial diversity. These results suggest that microbial composition could be involved in modulating these age-associated immune responses and thus may represent a potential therapeutic target.

Sex differences in the percentage of IRF5 positive B cells are associated with higher production of TNF-α in women in response to TLR9 in humans

BackgroundThe clinical course and outcome of many diseases differ between women and men, with women experiencing a higher prevalence and more severe pathogenesis of autoimmune diseases. The precise mechanisms underlying these sex differences still remain to be fully understood. IRF5 is a master transcription factor that regulates TLR/MyD88-mediated responses to pathogen-associated molecular patterns (PAMPS) in DCs and B cells. B cells are central effector cells involved in autoimmune diseases via the production of antibodies and pro-inflammatory cytokines as well as mediating T cell help. Dysregulation of IRF5 expression has been reported in autoimmune diseases, including systemic lupus erythematosus, primary Sjögren syndrome, and rheumatoid arthritis.MethodsIn the current study, we analyzed whether the percentage of IRF5 positive B cells differs between women and men and assessed the resulting consequences for the production of inflammatory cytokines after TLR7- or TLR9 stimulation.ResultsThe percentage of IRF5 positive B cells was significantly higher in B cells of women compared to men in both unstimulated and TLR7- or TLR9-stimulated B cells. B cells of women produced higher levels of TNF-α in response to TLR9 stimulation.ConclusionsTaken together, our data contribute to the understanding of sex differences in immune responses and may identify IRF5 as a potential therapeutic target to reduce harmful B cell-mediated immune responses in women.

Comparison of different methods of initiating lung inflammation and the sex-specific effects on inflammatory parameters.

Sex as a biological variable is an essential element of preclinical research. Sex-specific differences in lung volume, alveolar number, body weight, and the relationship between lung and body weight result in important questions about generating equivalent injuries in males and females so that comparisons in their responses can be assessed. Few studies compare stimulus dosing methods for murine lung models investigating immune responses. To examine sex-specific effects, we explored several dosing techniques for three stimuli, LPS, Streptococcus pneumoniae, and influenza A, on survival, injury parameters in bronchoalveolar lavage (BAL), and immune cell numbers in single-cell lung suspensions after injury. These data demonstrate that body weight-based dosing produced fewer differences between sexes when compared with injury initiated with inocula containing the same number of organisms. Comparison of the lung and body weights showed that females had a greater lung-to-body weight ratio than males. However, in LPS-induced injury, adjusting the dose for sex differences in this ratio in addition to body weight provided no new information about sex differences compared with dosing by body weight alone, most likely due to the variability in measures of the immune response. Studies evaluating BAL volumes revealed that smaller but more lavages resulted in greater returns and lower protein concentrations, particularly in the smaller female lungs. Thus, designing dosing and measurement methods that generate equivalent injuries facilitates comparison of immune responses between sexes. Continued development of methods for both induction and evaluation of injury will likely facilitate identification of sex differences in immune responses.

Sex bias in systemic lupus erythematosus: a molecular insight.

Acknowledging sex differences in immune response is particularly important when we consider the differences between men and women in the incidence of disease. For example, over 80% of autoimmune disease occurs in women, whereas men have a higher incidence of solid tumors compared to women. In general women have stronger innate and adaptive immune responses than men, explaining their ability to clear viral and bacterial infections faster, but also contributing to their increased susceptibility to autoimmune disease. The autoimmune disease systemic lupus erythematosus (SLE) is the archetypical sexually dimorphic disease, with 90% of patients being women. Various mechanisms have been suggested to account for the female prevalence of SLE, including sex hormones, X-linked genes, and epigenetic regulation of gene expression. Here, we will discuss how these mechanisms contribute to pathobiology of SLE and how type I interferons work with them to augment sex specific disease pathogenesis in SLE.

Sex differences in B cell frequencies and antibody responses following influenza vaccination in healthcare workers during the 2019–2020 season

Abstract Annual influenza vaccination for healthcare workers (HCWs) is required at Johns Hopkins to reduce influenza spread in healthcare facilities. We conducted a clinical study to evaluate sex differences in virus-specific antibody-producing B cells (i.e., plasmablasts) following receipt of the seasonal influenza vaccine in a highly vaccinated population of healthcare workers. To understand sex differences in immune responses to the influenza vaccine in the HCWs, 83 participants consented to blood draws at baseline and 75 participants returned for the 7- and 28-days post-vaccination survey and blood draw. Participants received their annual quadrivalent influenza vaccine (QIV). Influenza A specific plasmablasts were quantified at baseline and day 7 post-vaccination. Males had a significantly greater percentage of influenza-specific plasmablasts than females after vaccination (p<0.0003) Plasma collected at baseline and at day 28 post-vaccination was used to measure neutralizing antibody (nAb) titers against H1N1 and H3N2 vaccine viruses. Neutralizing antibody responses against either the H1N1 and H3N2 viruses increase after vaccination to the same degree in both males and females. The proportion of plasmablasts at day 7 was significantly associated with the vaccine-induced fold rise in nAb. This relationship differed by sex, whereby for a given proportion of plasmablasts, females tended to mount a greater fold-rise in nAb than males. These data suggest that despite having potentially fewer plasmablasts after vaccination, females mount an antiviral antibody response to the influenza vaccine viruses equivalent to males. Identification of transcriptional differences in plasmablasts from male and female HCWs is ongoing.

Hormones and Sex-Specific Medicine in Human Physiopathology.

A prodigious increment of scientific evidence in both preclinical and clinical studies is narrowing a major gap in knowledge regarding sex-specific biological responses observed in numerous branches of clinical practices. Some paradigmatic examples include neurodegenerative and mental disorders, immune-related disorders such as pathogenic infections and autoimmune diseases, oncologic conditions, and cardiovascular morbidities. The male-to-female proportion in a population is expressed as sex ratio and varies eminently with respect to the pathophysiology, natural history, incidence, prevalence, and mortality rates. The factors that determine this scenario incorporate both sex-associated biological differences and gender-dependent sociocultural issues. A broad narrative review focused on the current knowledge about the role of hormone regulation in gender medicine and gender peculiarities across key clinical areas is provided. Sex differences in immune response, cardiovascular diseases, neurological disorders, cancer, and COVID-19 are some of the hints reported. Moreover, gender implications in occupational health and health policy are offered to support the need for more personalized clinical medicine and public health approaches to achieve an ameliorated quality of life of patients and better outcomes in population health.

Estradiol Aggravate Nocardia farcinica Infections in Mice.

Males are generally more susceptible to Nocardia infection than females, with a male-to-female ratio of 2 and higher clinical disease. 17β-Estradiol has been implicated in affecting the sex-based gap by inhibiting the growth of N. brasiliensis in experiments, but the underlying mechanisms have not yet been fully clarified. In the present study, however, we report increased severity in N. farcinica IFM 10152-infected female mice compared with male mice with increased mortality, elevated lung bacterial loads and an exaggerated pulmonary inflammatory response, which was mimicked in ovariectomized female mice supplemented with E2. Similarly, the overwhelming increase in bacterial loads was also evident in E2-treated host cells, which were associated with downregulating the phosphorylation level of the MAPK pathway by binding the estrogen receptor. We conclude that although there are more clinical cases of Nocardia infection in males, estrogen promotes the survival of the bacteria, which leads to aggravated inflammation in females. Our data emphasize the need to include and separately analyze both sexes in future studies of Nocardia to understand the sex differences in immune responses and disease pathogenesis.

Delayed Antiviral Immune Responses in Severe Acute Respiratory Syndrome Coronavirus Infected Pregnant Mice.

Sex differences in immune responses had been reported to correlate with different symptoms and mortality in the disease course of coronavirus disease 2019 (COVID-19). However, whether severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection interferes with females’ fertility and causes different symptoms among pregnant and non-pregnant females remains unknown. Here, we examined the differences in viral loads, SARS-CoV-2-specific antibody titers, proinflammatory cytokines, and levels of T cell activation after SARS-CoV-2 sub-lethal infection between pregnant and non-pregnant human Angiotensin-Converting Enzyme II (ACE2) transgenic mouse models. Both mice showed elevated levels of viral loads in the lung at 4 days post-infection (dpi). However, viral loads in the pregnant group remained elevated at 7 dpi while decreased in the non-pregnant group. Consistent with viral loads, increased production of proinflammatory cytokines was detected from the pregnant group, and the IgM or SARS-CoV-2-specific IgG antibody in serum of pregnant mice featured delayed elevation compared with non-pregnant mice. Moreover, by accessing kinetics of activation marker expression of peripheral T cells after infection, a lower level of CD8+ T cell activation was observed in pregnant mice, further demonstrating the difference of immune-response between pregnant and non-pregnant mice. Although vertical transmission did not occur as SARS-CoV-2 RNA was absent in the uterus and fetus from the infected pregnant mice, a lower pregnancy rate was observed when the mice were infected before embryo implantation after mating, indicating that SARS-CoV-2 infection may interfere with mice’s fertility at a specific time window. In summary, pregnant mice bear a weaker ability to eliminate the SARS-CoV-2 virus than non-pregnant mice, which was correlated with lower levels of antibody production and T cell activation.

A biological approach to adult sex differences in skeletal indicators of childhood stress.

In previous work examining the etiology of cribra orbitalia (CO) and porotic hyperostosis (PH) in a contemporary juvenile mortality sample, we noted that males had higher odds of having CO lesions than females. Here, we examine potential reasons for this pattern in greater detail. Four non-mutually exclusive mechanisms could explain the observed sex differences: (1) sex-biased mortality; (2) sexual dimorphism in immune responses; (3) sexual dimorphism in bone turnover; or (4) sexual dimorphism in marrow conversion. The sample consists of postmortem computed tomography scans and autopsy reports, field reports, and limited medical records of 488 individuals from New Mexico (203 females; 285 males) aged between 0.5 and 15 years. We used Kaplan-Meier survival analysis, predicted probabilities, and odds ratios to test each mechanism. Males do not have lower survival probabilities than females, and we find no indications of sex differences in immune response. Overall, males have a higher probability of having CO or PH lesions than females. All results indicate that lesion formation in juveniles is influenced by some combination of sex differences in the pace of red-yellow conversion of the bone marrow and bone turnover. The preponderance of males with CO and PH likely speaks to the potential for heightened osteoblastic activity in males. We find no support for the hypotheses that sex biases in mortality or immune responses impacted lesion frequency in this sample. Sex differences in biological processes experienced by children may affect lesion formation and lesion expression in later life.

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

BackgroundMen are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known.Study design and methodsWe examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression.ResultsInitial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04–2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29–19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52–5.18, p = 0.009 in women, Pinteraction = 0.02).ConclusionsIn a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.

Addressing Sex and Gender Bias in COVID-19 Epidemiology in Bangladesh

Sex and gender are recognized as a vital factor in the infectious disease epidemiology, and disease outcomes, and these two factors also appear to hold for severe acute respiratory syndrome (SARS-CoV-2) infection. Evidence from COVID-19 infection in Bangladesh showed that a variation number of cases and deaths between the sex differences in immune responses to viruses and gender related risk factors among the male and female, but more severe outcomes in aged men of cases and deaths in 31~40 and 61~70 years respectively than female. However, the previous research dataset in the different parts of world evidenced that the men's are vulnerable compare to women's. Similar trends to observe in Bangladesh datasets in COVID-19 epidemiology. Male and female represented 71% and 29% of total reported confirmed COVID-19 cases in Bangladesh, respectively. Moreover, different levels of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMRSS2) enzymes play important role in COVID-19 infection of men and women. In addition, the effects of testosterone on ACE2 levels and the presence of ACE2 genes on the specific X-chromosome should not be ignored. In fine, this mini-review focuses on sex and gender variations in patients with an infectious disease of COVID-19 epidemiology in Bangladesh. The information of sex differences and age dependence might contribute to proper management and treatment of COVID-19 in Bangladesh.

Sex differences in immune responses to SARS-CoV-2 in patients with COVID-19.

Millions of people infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been diagnosed with coronavirus infectious disease 2019 (COVID-19). The prevalence and severity of COVID-19 differ between sexes. To explain these differences, we analyzed clinical features and laboratory values in male and female COVID-19 patients. The present study included a cohort of 111 people, i.e. 36 COVID-19 patients, 54 sex- and age-matched common viral community-acquired pneumonia (CAP) patients, and 21 healthy controls. Monocyte counts, lymphocyte subset counts, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels in the peripheral blood were analyzed. Higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, monocyte counts, and CRP and ALT levels were found in male COVID-19 patients. Decreased lymphocyte subset counts and proportions were observed in COVID-19 patients, except for the CD3+ and CD8+ T cell proportions. The lower CD4+ T cell proportions and higher CD8+ T cell proportions were observed in male and severe COVID-19 patients and the differences were independent of estrogen level. The CD4+ T cell proportion was negatively associated with the CD8+ T cell proportion in male COVID-19 patients; this correlation was non-significant in females. Our work demonstrates differences between sexes in circulating monocyte counts and CD4+ T cell and CD8+ T cell proportions in COVID-19 patients, independent of estrogen levels, are associated with the clinical manifestations in COVID-19 patients with high specificity.

Sex differences in immune responses.

Biological sex differences in immunity potentially underlie male bias for severe COVID-19

Are Low Testosterone and Sex Differences in Immune Responses Causing Mass Hysteria during the Coronavirus Pandemic?

By integrating the entire body of research in human sexual dynamics, immune responses, and sociocultural behavior, we can conclude that the mass hysteria our society is currently experiencing originates in our evolved psychological adaptations to pandemic conditions [i] . A lack of hormonal balance [ii] , due to a collapse in testosterone levels, may cause a disproportionate immune response that leads to the destruction of our cherished sociopolitical institutions—the very institutions that are design to protect human liberty and prosperity. What is playing out at a societal level is similar to an excessive immune response that causes the body to attack itself: decreased testosterone causing the kind of auto-immune response that is more prevalent in females. [i] Barzilai, R. (2020). Low Solar Activity, Winter Flu Conditions, Pandemics and Sex Wars: A Holistic View of Human Evolution. Science & Philosophy, 8(1). Doi: 10.23756/sp.v8i1.514 [ii] Barzilai, R. (2019). Solar cycles, light, sex hormones and the life cycles of civilization: Toward integrated chronobiology. Science & Philosophy, 7(2). doi: 10.23756/sp.v7i2.483

Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidities.

The high mortality rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is a critical concern of the coronavirus disease 2019 (COVID-19) pandemic. Strikingly, men account for the majority of COVID-19 deaths, with current figures ranging from 59% to 75% of total mortality. However, despite clear implications in relation to COVID-19 mortality, most research has not considered sex as a critical factor in data analysis. Here, we highlight fundamental biological differences that exist between males and females, and how these may make significant contributions to the male-biased COVID-19 mortality. We present preclinical evidence identifying the influence of biological sex on the expression and regulation of angiotensin-converting enzyme 2 (ACE2), which is the main receptor used by SARS-CoV-2 to enter cells. However, we note that there is a lack of reports showing that sexual dimorphism of ACE2 expression exists and is of functional relevance in humans. In contrast, there is strong evidence, especially in the context of viral infections, that sexual dimorphism plays a central role in the genetic and hormonal regulation of immune responses, both of the innate and the adaptive immune system. We review evidence supporting that ineffective anti-SARS-CoV-2 responses, coupled with a predisposition for inappropriate hyperinflammatory responses, could provide a biological explanation for the male bias in COVID-19 mortality. A prominent finding in COVID-19 is the increased risk of death with pre-existing cardiovascular comorbidities, such as hypertension, obesity, and age. We contextualize how important features of sexual dimorphism and inflammation in COVID-19 may exhibit a reciprocal relationship with comorbidities, and explain their increased mortality risk. Ultimately, we demonstrate that biological sex is a fundamental variable of critical relevance to our mechanistic understanding of SARS-CoV-2 infection and the pursuit of effective COVID-19 preventative and therapeutic strategies.