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

Sun, Mengying; Shankar, Rama; Ko, Meehyun; Chang, Christopher Daniel; Yeh, Shan-Ju; Li, Shilong; Liu, Ke; Zhou, Guoli; Xing, Jing; VanVelsen, Austin; VanVelsen, Tyler; Paithankar, Shreya; Feng, Benjamin Y.; Young, Krista; Strug, Michael; Turco, Lauren; Wang, Zichen; Schadt, Eric; Chen, Rong; Li, Xiaohong; Oskotsky, Tomiko; Sirota, Marina; Glicksberg, Benjamin S.; Nadkarni, Girish N.; Moeser, Adam J.; Li, Li; Kim, Seungtaek; Zhou, Jiayu; Chen, Bin

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.