PT  - JOURNAL ARTICLE
AU  - Joan C. Smith
AU  - Erin L. Sausville
AU  - Vishruth Girish
AU  - Monet Lou Yuan
AU  - Kristen M. John
AU  - Jason M. Sheltzer
TI  - Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract
AID  - 10.1101/2020.03.28.013672
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.28.013672
4099  - http://biorxiv.org/content/early/2020/04/26/2020.03.28.013672.short
4100  - http://biorxiv.org/content/early/2020/04/26/2020.03.28.013672.full
AB  - The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive-feedback loops that increase ACE2 levels and facilitate viral dissemination.Competing Interest StatementJ.C.S. is a co-founder of Meliora Therapeutics and is an employee of Google, Inc. This work was performed outside of her affiliation with Google and used no proprietary knowledge or materials from Google. J.M.S. has received consulting fees from Ono Pharmaceuticals, is a member of the Advisory Board of Tyra Biosciences, and is a co-founder of Meliora Therapeutics.