Estradiol reduces ACE2 and TMPRSS2 mRNA levels in A549 human lung epithelial cells

Epidemiologic studies suggest slightly higher risk of severe Covid-19 symptoms and fatalities following SARS-CoV-2 infection in men compared with women from similar age groups. This bias was suggested to reflect differences in the male and female immune system regulation, driven by different sex hormone levels in men and women, in particular, higher plasma estradiol in women. SARS-CoV-2 infects respiratory tract epithelial cells by binding to their cell membrane ACE2, followed by priming for cell entry by the host cell membrane serine protease TMPRSS2. The cell protease FURIN facilitates cell exit of mature SARS-CoV-2 virions. Our study examined the effects of in vitro treatment of A549 human lung epithelial cells with 17-β-estradiol on mRNA expression of genes coding for these proteins. Treatment of A549 human lung epithelial cells with 17-β-estradiol reduced the cellular mRNA levels of ACE2 and TMPRSS2 mRNA, while not affecting FURIN expression. Our findings suggest that 17-β-estradiol may reduce SARS-CoV-2 infection of lung epithelial cells, which may in part explain the reduced incidence of severe Covid-19 and fatalities among women compared with men of similar age. Studies into the molecular pathways by which 17-β-estradiol reduces ACE2 and TMPRSS2 mRNA expression in lung epithelial cells are needed for assessing its potential protective value against severe Covid-19.