Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones

Abstract

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.

Effects of SARS-CoV-2 on Cardiovascular System: The Dual Role of Angiotensin-Converting Enzyme 2 (ACE2) as the Virus Receptor and Homeostasis Regulator-Review

“…ACE2 expression is known to decrease with age and its reduction is stronger in males than females [ 43 , 44 ]. Because the ACE2 locus on the X-chromosome is only partially inactivated, in theory, females have double the dose of the ACE2 gene with respect to males [ 45 ]. The discrepancy in ACE2 expression between genders could be also explained by hormonal factors [ 46 , 47 ].…”

“…Furthermore, gender differences in susceptibility towards SARS-CoV-2 might be related to the immune response. In fact, many immune-associated genes (e.g., TLRs, RLRs) have an X-linked expression pattern, which is activated by hormones [ 45 ]. Specifically, estrogens have immuno-stimulant effects, while androgens are immunosuppressive [ 45 ].…”

“…In fact, many immune-associated genes (e.g., TLRs, RLRs) have an X-linked expression pattern, which is activated by hormones [ 45 ]. Specifically, estrogens have immuno-stimulant effects, while androgens are immunosuppressive [ 45 ]. Taken together, it is likely that the increase in ACE2 expression, reduced ACE2 cleavage and the more efficient immune response could contribute to lower SARS-CoV-2 susceptibility in females ( Figure 2 ).…”

Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

“…Studies of ACE2 are timely, especially in the context of its role as a cellular receptor for SARS-CoV-2 that facilitates viral cell entry [55]. CKD and male sex are risk factors for both SARS-CoV-2 infection and COVID-19 disease severity [42,[56][57][58]. Although acute kidney injury is a common complication of severe COVID-19 [58], the role of direct viral infection of the kidney is not well understood [59,60].…”

Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies

“…Additionally, AR is associated with COVID comorbidities (Dolan et al, 2020), and recently implicated in the severity of COVID-19 in women with polycystic ovarian syndrome, a disorder associate with high androgen levels and androgen sensitivity (Gotluru, Roach, Cherry, & Runowicz, 2021). Our ERC finding that indicates ACE2 and AR coevolution suggests a regulatory feedback between these two proteins, which could be relevant to COVID-19 severity and other sex differential pathologies, such as cardiovascular disease sex hormone related pathologies (Viveiros et al, 2021). Other notable significant ACE2 ERCs (Table 1) include Metabolism regulating signaling molecule D (FAM3D), Transmembrane -protein 63C (TMEM63C); Collagen Type IV Alpha 4 (COL4A4), L1 cell adhesion molecule (L1CAM), and ITPRIP-like (ITPRIPL2).…”