Tags

Type your tag names separated by a space and hit enter

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.
Cell. 2020 07 23; 182(2):429-446.e14.Cell

Abstract

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

Authors+Show Affiliations

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Protein Expression and Purification Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH, USA.Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.Department of Microbiology and Immunology, Canadian Center for Vaccinology, Dalhousie University, Halifax, NS, Canada; Laboratory of Immunology, Shantou University Medical College, Shantou, Guangdong, China.Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Pathology, University of New Mexico, Albuquerque, NM, USA.Division of Pulmonary and Critical Care Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.Department of Pathology, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.Department of Pathology, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA.Department of Cell Biology, Regeneration Next Initiative, Duke University Medical Center, Durham, NC, USA.Department of Cell Biology, Regeneration Next Initiative, Duke University Medical Center, Durham, NC, USA.Department of Otolaryngology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: richard_boucher@med.unc.edu.Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: rbaric@email.unc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32526206

Citation

Hou, Yixuan J., et al. "SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract." Cell, vol. 182, no. 2, 2020, pp. 429-446.e14.
Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell. 2020;182(2):429-446.e14.
Hou, Y. J., Okuda, K., Edwards, C. E., Martinez, D. R., Asakura, T., Dinnon, K. H., Kato, T., Lee, R. E., Yount, B. L., Mascenik, T. M., Chen, G., Olivier, K. N., Ghio, A., Tse, L. V., Leist, S. R., Gralinski, L. E., Schäfer, A., Dang, H., Gilmore, R., ... Baric, R. S. (2020). SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell, 182(2), 429-e14. https://doi.org/10.1016/j.cell.2020.05.042
Hou YJ, et al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell. 2020 07 23;182(2):429-446.e14. PubMed PMID: 32526206.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. AU - Hou,Yixuan J, AU - Okuda,Kenichi, AU - Edwards,Caitlin E, AU - Martinez,David R, AU - Asakura,Takanori, AU - Dinnon,Kenneth H,3rd AU - Kato,Takafumi, AU - Lee,Rhianna E, AU - Yount,Boyd L, AU - Mascenik,Teresa M, AU - Chen,Gang, AU - Olivier,Kenneth N, AU - Ghio,Andrew, AU - Tse,Longping V, AU - Leist,Sarah R, AU - Gralinski,Lisa E, AU - Schäfer,Alexandra, AU - Dang,Hong, AU - Gilmore,Rodney, AU - Nakano,Satoko, AU - Sun,Ling, AU - Fulcher,M Leslie, AU - Livraghi-Butrico,Alessandra, AU - Nicely,Nathan I, AU - Cameron,Mark, AU - Cameron,Cheryl, AU - Kelvin,David J, AU - de Silva,Aravinda, AU - Margolis,David M, AU - Markmann,Alena, AU - Bartelt,Luther, AU - Zumwalt,Ross, AU - Martinez,Fernando J, AU - Salvatore,Steven P, AU - Borczuk,Alain, AU - Tata,Purushothama R, AU - Sontake,Vishwaraj, AU - Kimple,Adam, AU - Jaspers,Ilona, AU - O'Neal,Wanda K, AU - Randell,Scott H, AU - Boucher,Richard C, AU - Baric,Ralph S, Y1 - 2020/05/27/ PY - 2020/04/24/received PY - 2020/05/11/revised PY - 2020/05/20/accepted PY - 2020/6/12/pubmed PY - 2020/7/31/medline PY - 2020/6/12/entrez KW - ACE2 KW - COVID-19 KW - SARS-CoV-2 KW - infectious clone KW - nasal infection KW - neutralization assay KW - primary cells KW - reporter virus KW - respiratory tropism KW - reverse genetics SP - 429 EP - 446.e14 JF - Cell JO - Cell VL - 182 IS - 2 N2 - The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32526206/SARS_CoV_2_Reverse_Genetics_Reveals_a_Variable_Infection_Gradient_in_the_Respiratory_Tract_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(20)30675-9 DB - PRIME DP - Unbound Medicine ER -