SARS-CoV-2 pathology and links to sex steroids
Direct antigen testing and seroprevalence studies both support equivalent rates of SARS-CoV-2 infection between men and women, but whether men then go onto exhibit larger viral loads is unknown. The possibility of sex-specific differences in efficiency of viral entry, and replication was suggested from inoculation studies of SARS-CoV virus, in which viral titres were greater in lungs of infected male mice as compared to females despite equivalent inoculation loads3. This is biologically plausible as the transmembrane serine protease 2 (TMPRSS2) which SARS-CoV-2 uses for S protein priming, is down-regulated by oestradiol and strongly upregulated in lung cell lines by androgens at concentrations regularly found in men. There is less clarity over modulation of angiotensin-converting enzyme 2 (ACE2) – the cell entry receptor engaged by SARS-CoV-2, as this is down regulated in the kidneys but not in lungs by 17β oestradiol, and is induced in human atrial tissue by oestradiol4. However, whether tissue specific differences in oestradiol dependent ACE2 expression may contribute to sex-specific differences observed in extrapulmonary complications is still untested for SARS-CoV-21.
Sexual discordance in the progression of respiratory infections is well recognised, and the less severe COVID19 progression observed in females may be attributable to the differential regulation of sex hormones on innate immune cells in the lungs, which will impact on both the initial proinflammatory / effector phase but then also resolution/repair phase which will drive subsequent complications 5. Direct experimental evidence for a hormonally mediated discordant immune response for coronaviruses was derived from a mouse model of SARS-CoV, with male mice exhibiting enhanced vascular leakage and alveolar oedema as compared to female counterparts 3. These histological changes were accompanied by increased accumulation of inflammatory monocyte macrophages (IMM) and neutrophils in the lungs, with experimental IMM depletion reducing male mortality. That oestrogen and not androgens mediated these sex specific differences, was supported by ovariectomy or treatment with an oestrogen receptor antagonist, as both increased female mortality with a concomitant increase in pulmonary IMMs. In contrast, male gonadectomy or treatment with an anti-androgen, did not alter male disease outcome3. Detailed immune phenotyping of exposed individuals will further enlighten the sex-specific innate and adaptive immune responses that will support vaccine development.