What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

Abstract

The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.

COVID-19 and Systemic Lupus Erythematosus: Focus on Immune Response and Therapeutics

“…Studies of demographic factors including ethnicity and sex have suggested that specific populations may be predisposed to more severe SLE and COVID-19 disease presentation (24). Men experience greater hospitalization and mortality rates due to COVID-19 while women experience greater incidence rates of SLE.…”

“…This finding is consistent with the observation that men are biased towards infections, while women are biased towards autoimmune disorders. It has been postulated that hormonal factors which heighten ability to clear infection may also increase likelihood of autoimmune disease in women (24). Additional contributions from genetic components and microbiota may cause women to produce more pro-inflammatory cytokines which, in turn, may lead to a more aggressive immune response (24).…”

“…It has been postulated that hormonal factors which heighten ability to clear infection may also increase likelihood of autoimmune disease in women (24). Additional contributions from genetic components and microbiota may cause women to produce more pro-inflammatory cytokines which, in turn, may lead to a more aggressive immune response (24). While the process by which race and ethnicity influence risk is less clear, evidence suggests that SLE and COVID-19 disproportionately affect racial and ethnic minorities and result in worse outcomes in people of color.…”

“…This is evidenced by the more than doubled COVID-19 mortality rate observed in men compared to women, despite sometimes similar prevalence across gender (26). Studies indicate a possible genetic basis to this disparity, as many immune-related genes are X chromosome-linked (24). Typically, the silencing of one copy of the X chromosome occurs in women to ensure similar gene dosage between sexes.…”

“…Typically, the silencing of one copy of the X chromosome occurs in women to ensure similar gene dosage between sexes. However, some genes may fail to undergo silencing and thus escape inactivation, producing biallelic expression of gene product (24). Biallelic expression of immune-related genes has been shown to increase T-and B-cell activation, which may both predispose women to SLE and provide protective advantages in the COVID-19 immune response.…”