Estrogen Hormone Is an Essential Sex Factor Inhibiting Inflammation and Immune Response in COVID-19

Although vaccines have been evaluated and approved for SARS-CoV-2 infection prevention, there remains a lack of effective treatments to reduce the mortality of COVID-19 patients already infected with SARS-CoV-2. The global data of COVID-19 showed that men have a higher mortality rate than women. We further observed that the proportion of mortality of female increases starting from around the age of 55 significantly. Thus, sex is an essential factor associated with COVID-19 mortality, and sex related genetic factors could be interesting mechanisms and targets for COVID-19 treatment. However, the associated sex factors and signaling pathways remain unclear. Here, we propose to uncover the potential sex associated factors using systematic and integrative network analysis. The unique results indicated that estrogen hormones (ER), e.g., estrone and estriol, 1) interacting with ESR1/2 receptors, 2) can inhibit SARS-CoV-2 caused inflammation and immune response signaling in host cells; and 3) estrogen hormone is associated with the distinct fatality rates between male and female COVID-19 patients. Specifically, a high level of estradiol protecting young female COVID-19 patients, and estrogen loss to an extremely low level in females after about 55 years of age causing the increased fatality rate of women. In conclusion, estrogen hormone, interacting with ESR1/2 receptors, is an essential sex factor that protects COVID-19 patients by inhibiting inflammation and immune response caused by SARS-CoV-2 infection. Medications perturb the down-stream of ESR1/ESR2 to inhibit the inflammation and immune response can be effective or synergistic combined with other existing drugs for COVID-19 treatment.