Impact of Sex and Gender on COVID-19 outcomes: Role of ACE-2, TMPRSS2, and gender-specific risk factors

Background: Switzerland is among the countries with the highest number of coronavirus disease-2019 (COVID-19) cases per capita in the world. Emerging evidence from China suggests that COVID-19 is deadlier for infected men than women, with a 2.8 percent fatality rate being reported in Chinese men versus 1.7 percent in women. Further, sex-disaggregated data for COVID-19 show a higher number of cases in men as compared to women. Mortality is highest in aged men and men with pre-existing cardiovascular disease. The mechanisms for the reduced reported cases and case fatality rate in women are currently unclear but may offer potential to develop novel risk stratification tools and therapeutic options for women and men.Aims and methods: We aim to analyse the available clinical and epidemiological data to confirm a reduced susceptibility of women towards COVID-19. We will clarify protective mechanisms in females by assessing clinical variables and verifying cellular and molecular key pathways in a murine model of sex hormone withdrawal, where tissue samples are already available. We hypothesize that sex related factors, such as sex hormone-driven innate and adaptive immune responses as well as hormone-regulated expression of genes encoding for the SARS-CoV2 entry receptors angiotensin converting enzyme (ACE)-2 receptor and the cellular serine protease TMPRSS2 are involved. Furthermore, gender-specific lifestyle behaviour such as smoking, psychological stress, and socioeconomic conditions will be included. Specific demographic groups including male patients on anti-androgenic treatment for prostate cancer or women receiving hormone treatment will be assessed in a prospective observational cohort study performed at the University Hospitals Zurich, Basel, and Bern. We expect that the risk of disease transmission and manifestation varies depending on sex hormone status. Further, the influence of female and male sex hormones, postmenopausal hormone replacement therapy (HRT), number of pregnancies and hormonal contraception on COVID-19 disease severity and outcome will be assessed. The acquisition of blood samples from severely ill patients hospitalized for COVID-19 will allow analysis of inflammatory profiles and their interaction with sex- and gender-specific variables. Finally, existing tissue samples from gonadectomized or sham operated young, middle aged and senescent mice of both sexes will provide information on whether the expression of ACE2 and TMPRSS2 in heart and lungs depends on age, sex, hormonal status and their interaction. Relevance and Impact: Gender disparities observed in COVID-19 vulnerability clearly emphasize the need to understand the impact of sex and gender on incidence and case fatality of the disease so that timely treatment in highly vulnerable demographic groups can be tailored to their specific needs. The proposed project will combine clinical data from ongoing cohort studies with experimental work in mice. This strategy allows rapid analysis of data and implementation of results. Our work will identify both, sex- and gender-related predictors of severe variants of COVID-19 and has the potential to identify effective therapeutic interventions.