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.