@article{0f9fec1342c3467088b027e947623f28,
title = "Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers",
abstract = "Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers.",
keywords = "ACE2, COVID-19, IFN-β1, SARS-CoV-2, TMPRSS2, ciliated epithelial cell, nasal cavity, smoking, trachea, upper airway",
author = "Tsuguhisa Nakayama and Lee, {Ivan T.} and Sizun Jiang and Matter, {Matthias S.} and Yan, {Carol H.} and Overdevest, {Jonathan B.} and Wu, {Chien Ting} and Yury Goltsev and Shih, {Liang Chun} and Liao, {Chun Kang} and Bokai Zhu and Yunhao Bai and Peter Lidsky and Yinghong Xiao and David Zarabanda and Angela Yang and Meena Easwaran and Sch{\"u}rch, {Christian M.} and Pauline Chu and Han Chen and Stalder, {Anna K.} and McIlwain, {David R.} and Borchard, {Nicole A.} and Gall, {Phillip A.} and Dholakia, {Sachi S.} and Wei Le and Le Xu and Tai, {Chih Jaan} and Yeh, {Te Huei} and Elizabeth Erickson-Direnzo and Duran, {Jason M.} and Mertz, {Kirsten D.} and Hwang, {Peter H.} and Haslbauer, {Jasmin D.} and Jackson, {Peter K.} and Thomas Menter and Raul Andino and Canoll, {Peter D.} and DeConde, {Adam S.} and Patel, {Zara M.} and Alexandar Tzankov and Nolan, {Garry P.} and Nayak, {Jayakar V.}",
note = "Funding Information: The authors sincerely appreciate the generosity of tissue donation from the deceased individuals and their families which enabled this study. We thank members of the Nayak and Nolan labs for critical and thoughtful discussions. This work was supported by the California Institute for Regenerative Medicine (DISC2-09637 to J.V.N.), the Defense Advanced Research Projects Agency (HR001118S0037-PREPARE-FP-001 to J.V.N.), the Stanford Initiative to Cure Hearing Loss (SICHL) (to J.V.N.), the PDev Foundation (to J.V.N.), the Parker Institute for Cancer Immunotherapy (to G.P.N.), the Food and Drug Administration (HHSF223201610018C and DSTL/AGR00980 to G.P.N.), Fast Grant Funding for COVID-19 Science (to G.P.N.), Botnar Research Centre for Child Health Emergency Response to COVID-19 grant (to S.J. C.M.S. D.R.M. T.M. G.P.N. M.S.M. and A.T.), Bill and Melinda Gates Foundation COVID-19 Pilot Award (to S.J. D.R.M. and G.P.N.), the National Institutes of Health (R01HL151677 to J.V.N. 1R01AI149672-01 to G.P.N. and U54-CA209971 to G.P.N.), the Rachford and Carlotta A. Harris Endowed Chair (to G.P.N.), Stanford Translational Research and Applied Medicine (TRAM) Pilot Grant (to I.T.L.), Thrasher Research Fund Early Career Award (to I.T.L.), Stanford Maternal and Child Health Research Institute (MCHRI) Clinical (MD) Trainee Support Award (to I.T.L. an Ernest and Amelia Gallo Endowed Postdoctoral Fellow), the Leukemia and Lymphoma Society Career Development Program (to S.J.), Stanford COVID-19 Crisis Response grant (to I.T.L. S.J. C.-T.W. and T.N.), and the Swiss National Science Foundation (SNSF; 320030_189275 to M.S.M.). I.T.L. conceived and coordinated the study. T.N. I.T.L. and S.J. designed and performed the experiments. S.J. performed the single-cell RNA-seq analysis. T.N. performed the microscopy imaging. M.S.M. C.H.Y. J.B.O. P.C. L.X. A.K.S. J.M.D. K.D.M. J.D.H. T.M. P.D.C. A.S.D. and A.T. acquired informed consent, acquired and processed COVID-19 tissue specimen, and/or collected clinical data. T.N. I.T.L. L.-C.S. C.-K.L. D.Z. A.Y. P.C. N.A.B. P.A.G. S.S.D. W.L. C.-J.T. T.-H.Y. Z.M.P. P.H.H. and J.V.N. acquired informed consent and acquired and/or processed normal human tissue specimens. M.S.M. C.M.S. and A.T. evaluated the histology of tissue specimens. C.-T.W. P.L. Y.X. P.K.J. and R.A. performed/supervised ex vivo infection experiments and contributed validation reagents. Y.G. developed and performed computational image processing. T.N. I.T.L. S.J. and Y.B. analyzed the data. T.N. conducted statistical analyses. B.Z. D.Z. M.E. H.C. and E.E.-D. provided experimental assistance. T.N. I.T.L. and S.J. designed and prepared the final figures. I.T.L. and S.J. wrote the manuscript with significant contributions from T.N. M.S.M. C.H.Y. J.B.O. A.T. G.P.N. and J.V.N. Funding and supervision were provided by T.N. I.T.L. S.J. M.S.M. C.-T.W. D.R.M. P.K.J. A.T. G.P.N. and J.V.N. All authors reviewed and agreed with the content of this manuscript. I.T.L. is currently an employee and shareholder of Moderna, although this work was conducted prior to/independent of his employment. I.T.L. had also received research support unrelated to this study from Genentech (Roche). Moderna did not fund or participate in this study in any form. Funding Information: The authors sincerely appreciate the generosity of tissue donation from the deceased individuals and their families which enabled this study. We thank members of the Nayak and Nolan labs for critical and thoughtful discussions. This work was supported by the California Institute for Regenerative Medicine ( DISC2-09637 to J.V.N.), the Defense Advanced Research Projects Agency ( HR001118S0037-PREPARE-FP-001 to J.V.N.), the Stanford Initiative to Cure Hearing Loss (SICHL) (to J.V.N.), the PDev Foundation (to J.V.N.), the Parker Institute for Cancer Immunotherapy (to G.P.N.), the Food and Drug Administration ( HHSF223201610018C and DSTL/AGR00980 to G.P.N.), Fast Grant Funding for COVID-19 Science (to G.P.N.), Botnar Research Centre for Child Health Emergency Response to COVID-19 grant (to S.J., C.M.S., D.R.M., T.M., G.P.N., M.S.M., and A.T.), Bill and Melinda Gates Foundation COVID-19 Pilot Award (to S.J., D.R.M., and G.P.N.), the National Institutes of Health ( R01HL151677 to J.V.N., 1R01AI149672-01 to G.P.N., and U54-CA209971 to G.P.N.), the Rachford and Carlotta A. Harris Endowed Chair (to G.P.N.), Stanford Translational Research and Applied Medicine (TRAM) Pilot Grant (to I.T.L.), Thrasher Research Fund Early Career Award (to I.T.L.), Stanford Maternal and Child Health Research Institute (MCHRI) Clinical (MD) Trainee Support Award (to I.T.L., an Ernest and Amelia Gallo Endowed Postdoctoral Fellow), the Leukemia and Lymphoma Society Career Development Program (to S.J.), Stanford COVID-19 Crisis Response grant (to I.T.L., S.J., C.-T.W., and T.N.), and the Swiss National Science Foundation (SNSF; 320030_189275 to M.S.M.). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = oct,
day = "19",
doi = "10.1016/j.xcrm.2021.100421",
language = "English (US)",
volume = "2",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "10",
}