Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response
Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response
SUMMARY 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.
Purkayastha Arunima、Sen Chandani、Langerman Justin、Mulay A.、Konda B.、Arumugaswami Vaithilingaraja、Garcia Gustavo Jr.、Sim Myung S.、Stripp Barry R.、Rickabaugh Tammy M.、Meneses Luisa K.、Gomperts Brigitte N.、Shia David W.、Vijayaraj Preethi、Plath Kathrin
UCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of MedicineUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of MedicineDepartment of Biological Chemistry, David Geffen School of MedicineLung and Regenerative Medicine Institutes, Cedars-Sinai Medical CenterLung and Regenerative Medicine Institutes, Cedars-Sinai Medical CenterDepartment of Molecular and Medical Pharmacology, University of California||Jonsson Comprehensive Cancer CenterDepartment of Molecular and Medical Pharmacology, University of CaliforniaUCLA Department of MedicineLung and Regenerative Medicine Institutes, Cedars-Sinai Medical CenterUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of MedicineUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of MedicineUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine||Department of Molecular Biology Interdepartmental Program||Jonsson Comprehensive Cancer Center||Eli and Edythe Broad Stem Cell Research Center||Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of MedicineUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine||UCLA Medical Scientist Training Program, David Geffen School of Medicine||Department of Molecular Biology Interdepartmental ProgramUCLA Children?ˉs Discovery and Innovation Institute, Mattel Children?ˉs Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine||UCLA Medical Scientist Training Program, David Geffen School of MedicineDepartment of Biological Chemistry, David Geffen School of Medicine||Department of Molecular Biology Interdepartmental Program||Jonsson Comprehensive Cancer Center||Eli and Edythe Broad Stem Cell Research Center||Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine
基础医学生物科学研究方法、生物科学研究技术生理学
Purkayastha Arunima,Sen Chandani,Langerman Justin,Mulay A.,Konda B.,Arumugaswami Vaithilingaraja,Garcia Gustavo Jr.,Sim Myung S.,Stripp Barry R.,Rickabaugh Tammy M.,Meneses Luisa K.,Gomperts Brigitte N.,Shia David W.,Vijayaraj Preethi,Plath Kathrin.Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response[EB/OL].(2025-03-28)[2025-06-08].https://www.biorxiv.org/content/10.1101/2020.07.28.226092.点此复制
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