PT  - JOURNAL ARTICLE
AU  - Arunima Purkayastha
AU  - Chandani Sen
AU  - Gustavo Garcia, Jr.
AU  - Justin Langerman
AU  - Preethi Vijayaraj
AU  - David W. Shia
AU  - Luisa K. Meneses
AU  - Tammy M. Rickabaugh
AU  - A. Mulay
AU  - B. Konda
AU  - Myung S. Sim
AU  - Barry R. Stripp
AU  - Kathrin Plath
AU  - Vaithilingaraja Arumugaswami
AU  - Brigitte N. Gomperts
TI  - Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response
AID  - 10.1101/2020.07.28.226092
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.28.226092
4099  - http://biorxiv.org/content/early/2020/07/29/2020.07.28.226092.short
4100  - http://biorxiv.org/content/early/2020/07/29/2020.07.28.226092.full
AB  - Most demographic studies are now associating current smoking status with increased risk of severe COVID-19 and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon β-1 abrogated the viral infection, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.Competing Interest StatementThe authors have declared no competing interest.