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

Abstract

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.

Keywords: COVID-19; Cardiovascular comorbidities; Inflammation; SARS-CoV-2; Sex differences.

Figure 1

Potential mechanisms of how sexual dimorphism results in higher mortality of COVID-19 in males. SARS-CoV-2 enters cells via binding to the cellular ACE2 receptor and subsequent spike protein cleavage by TMPRSS2 mediating fusion of viral and cellular membranes. Current data suggest that ACE2 expression levels are the same in both sexes. Infection rates are similar between men and women, however, the response to infection differs between the sexes. Anti-viral responses and viral clearance, mediated by IFN and TLR7, are postulated to be increased in females and may be one of the key mechanisms behind the reduced mortality observed in women compared with men in COVID-19. Dysregulated inflammation and increased cytokine release are potential links to increased ARDS, respiratory failure, and cardiovascular comorbidities in males, culminating in increased mortality. ACE2, angiotensin-converting enzyme 2; ARDS, acute respiratory distress syndrome; CCL2, C-C chemokine ligand 2; F, female; IFN, interferon; IL-6, interleukin 6; M, male; TLR7, toll-like receptor 7; TMPRSS2, Transmembrane Serine Protease 2.