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.

Keywords: COVID-19; SARS-CoV; coronavirus; gender; immune response; infection immunity; sex.

FIGURE 1

Overview of sex-based differences in the immune response to Infections. Schematic shows how genes, sex hormones, and microbiome may influence sex-based differences in the host immune responses to infections, determining susceptibility, disease course, and clinical outcomes.

FIGURE 2

Innate and adaptive immune responses in SARS-CoV-2 Infection. Schematic shows a lung alveolus and a blood vessel. The left side of the figure describes effects of the innate immune system specifically in men, while the right side depicts their delayed adaptive immune functions. Dotted arrows represent a decrease in function or activity, while triple headed solid arrows signify an increase compared to infection in women. The most implicated cell types and their associated cytokines have been shown. In men, the novel coronavirus infection has reduced activation of APC and early proinflammatory processes. A decrease in this pathway causes delayed, excessive proinflammatory cytokine responses leading to the infamous cytokine storm implicated in both components of immunity.

FIGURE 3

Immune-related Genes implicated in the sex-based differences in the immune response. Schematic shows genes encoded on the X-chromosome and chromosome 6. Table lists the role of these genes in innate and/or adaptive immunity and mechanism of action. Genes indicated in blue text escape X chromosome inactivation, while those that do not undergo escape are indicated in red. NEMO is marked with an asterisk (*) to specify skewed X chromosome inactivation.

FIGURE 4

ACE2 receptor expression in tissues. ACE-2 receptor expression is found in the lung type 2 pneumocytes, heart endocardial cells, blood vessel endothelial cells, kidney tubular epithelial cells, and intestinal enterocytes. There is evidence that estrogen has a protective function on ACE-2 receptor expression in these tissues, while male sex is correlated with an upregulation of ACE-2 receptors in these tissues. SARS-CoV-2 is able to bind to the ACE-2 receptor via ionic interactions between Lys317 on the virus and Asp30 on the receptor and via Van der Waals interactions between Leu472 on the virus and Met82 on the receptor.