The impact of sex in determining tolerance to coronavirus infection

Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), and -2 (SARS-CoV-2) are highly pathogenic coronaviruses (CoVs) causing disease ranging from asymptomatic to lethal in humans. The host's infection response determines disease severity. Tolerant hosts mount a controlled immune response, displaying mild illness; a dysregulated response may lead to severe disease. Comparing tolerant and severe host responses helps to understand the underlying mechanisms that lead to differential outcomes to infection. Epidemiological data for these CoVs indicate that males have a higher case fatality rate than females. One hypothesized mechanism of tolerance to CoV infection is differences in dihydrotestosterone (DHT) and 17β-estradiol (E2) sex hormone signalling. Prior studies identified differences in sex hormone signalling associated with tolerance in MERS-CoV infection in animal models. E2 may play a protective role while DHT may have an immunosuppressive effect in SARS-CoV-2 infection; however, the underlying mechanism is unknown. The effect of sex hormones in MERS-CoV and SARS-CoV-1 has not been assessed. I propose investigating the role of sex in determining tolerance to CoV infection. We will analyze transcriptomic data from tolerant and severe models of MERS-CoV infection to interrogate distinct responses driven by sex hormones. To further investigate the impact of sex hormones, we will treat cells with E2 or DHT then infect with SARS-CoV-1, -2 or MERS-CoV to observe effects on viral entry and replication and induction of host inflammatory signalling. This study will clarify the role of sex hormones during CoV infection and assess if sex determines CoV replication and pathogenicity.