Why Are Less Women Than Men Dying of COVID-19?
Both young and old women are dying less than matched age males. Beside hormone differences, which, however, do not appear to be the only factor, there are different potential mechanisms that may explain why women are less prone to severe COVID-19 infections.
The expression and activity of two factors may be considered, namely angiotensin-converting enzyme-2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) [Cheng et al. 2015; Kuba et al 2005]. While ACE2 is the receptor for the spike (S) protein of coronaviruses, TMPRSS2 splits the S-protein at sites S1/S2 and S2, favoring the attachment and fusion of the virus to cell membranes, respectively. ACE2 is largely expressed in organs mainly targeted and damaged by SARS-CoV-2 [Pagliaro and Penna 2005]. Both ACE2 and TMPRSS2 have been proposed as modulators of the different susceptibility to SARS-CoV in both sexes [Hoffmann et al. 2020]. Indeed, the expression of ACE2 seems reduced in post-menopausal women. However, in some studies, no differences were detected for ACE and ACE2 between the 2 sexes, while a lower ACE2 serum activity was observed in younger compared to older women [Fernández-Atucha et al. 2017]. ACE2 is located on the X chromosome, and is one of the genes escaping X inactivation [Tukiainen et al. 2017]. Therefore, it can be hypothesized that the second X chromosome could protect women from fatal polymorphisms that make the infection more aggressive in males, e.g. by favoring viral binding. Indeed, in a recent study, worse outcome in older COVID-19 patients has been attributed to the presence of lower ACE-2 levels and the subsequent upregulation of Angiotensin II (Ang II) proinflammatory pathways throughout the body, which could make patients more prone to systemic “deleterious” effects of Ang II [AlGhatrif et al. 2020]. ACE and ACE2 and their major products, Ang II and Ang-1-7, respectively, are linked in a sort of ying/yang process, when one decreases the other increases and viceversa [Pagliaro and Penna 2005; Koni and Miyamori 2007; Wakahara et al. 2016; Wang et al. 2015, 2016]. Whether ACE2 levels in the lung are related to the susceptibility and severity of COVID-19 infection is a matter of investigation [Gheblawi et al. 2020], and men may have higher expression of ACE2 in the lungs compared to women [Zhao et al. 2020], with potential important consequences on COVID-19 infections. Moreover, the different roles of membrane bound ACE2 and circulating ACE2 should be considered. Indeed, it has been proposed that soluble ACE2 could quench the coronavirus by limiting its attachment to cellular ACE2 [Monteil et al. 2020]. It is unknown whether circulating ACE2 levels in the two sexes are different. This would be an important piece of information as circulating ACE2 quenching the virus may limit the possibility for the virus to target other organs.
Although some animal and human studies suggest that TMPRSS2 is involved in determining severity of influenza [Cheng et al. 2015; Sakai et al. 2015], its role during coronavirus infections and in the modulation of COVID-19 severity is still unclear. Nevertheless, we must consider that TMPRSS2 is a testosterone regulated gene and may have a higher expression in men than in women [Tomlins et al. 2005].
Moreover, several other X-linked genes (such as ILs, FOXP3XIST, TLR7) and Y-linked genes (SRY, SOX9) may explain sex differences [Ghosh and Klein 2017]. These and other immune regulatory genes encoded by the X and Y chromosomes may explain lower viral loads and reduced inflammation in women compared to men [Conti and Younes 2020]. In particular, the two X chromosomes seem to regulate the immune system even if one of them is inactive. The X chromosome regulates the immune system also acting on other proteins, including CD40L, CXCR3 and TLR8. These can be up-regulated in women and can determine the response to viral infections as well as to vaccinations. A Differentially Expressed Genes (DEGs) network was constructed to identify a specific gene signature characterizing SARS-CoV-2 infection [Fagone et al. 2020]. Intriguingly, ten DEGs were modulated by sexual hormones, as Androgen Receptor regulated 6 DEGs (while CCL20 and CXCL1 genes were upregulated; THBD, HEY2, BBOX1 and MYLK were downregulated genes); whereas Estrogen Receptor 1 regulates 4 DEGs (while C3 and EDN1 genes were upregulated; PDK4 and VTCN1 were downregulated DEGs). Also, CD4+ T cells number differs between sexes being higher in women with a better immune response [Conti and Younes 2020]. Finally, the number of sex-independent non-genetic factors that can change susceptibility and mortality is enormous, and many other factors are likely to be considered, including gender and cultural habits in different countries. For example, an Outbreak in the Republic of Korea determined a high incidence of case in women due to social and religious events occurring in those days. [Report on the Epidemiological Features of Coronavirus Disease 2019 (COVID-19) Outbreak in the Republic of Korea from January 19 to March 2, 2020].