Sex differences in viral entry protein expression, host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment in COVID-19

Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the expression of entry genes ACE2 and TMPRSS2 , host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment. Using over 220,000 human gene expression profiles covering a wide range of age, tissues, and diseases, we found that male samples show higher expression levels of ACE2 and TMPRSS2 , especially in the older group (>60 years) and in the kidney. Analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present profound expression differences in responses to SARS-CoV-2. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Finally, we observed selective Estrogen Receptor modulators, but not other hormone drugs (agonists/antagonists of estrogen, androgen, and progesterone), could reduce SARS-CoV-2 Infection in vitro.