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      SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

      1 , 19 , 3 , 19 , 1 , 19 , 1 , 19 , 3 , 2 , 3 , 3 , 1 , 3 , 3 , 16 , 17 , 1 , 1 , 1 , 1 , 3 , 3 , 3 , 3 , 3 , 3 , 4 , 11 , 12 , 10 , 18 , 2 , 2 , 5 , 6 , 5 , 5 , 13 , 14 , 15 , 15 , 9 , 9 , 7 , 8 , 3 , 3 , 3 , , 1 , 2 , 20 ,

      Cell

      Elsevier Inc.

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          Summary

          The mode of acquisition and causes for the variable clinical spectrum of COVID-19 remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore 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 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) vs 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.

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          Author and article information

          Contributors
          Journal
          Cell
          Cell
          Cell
          Elsevier Inc.
          0092-8674
          1097-4172
          27 May 2020
          27 May 2020
          Affiliations
          [1 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [2 ]Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [3 ]Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [4 ]Protein Expression and Purification Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [5 ]Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [6 ]HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [7 ]Department of Otolaryngology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [8 ]Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
          [9 ]Department of Cell Biology, Regeneration Next Initiative, Duke University Medical Center, Durham, NC, USA
          [10 ]Department of Microbiology and Immunology, Canadian Center for Vaccinology, Dalhousie University, Halifax, NS, Canada
          [11 ]Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH, USA
          [12 ]Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
          [13 ]Department of Pathology, University of New Mexico, Albuquerque, NM, USA
          [14 ]Division of Pulmonary and Critical Care Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA
          [15 ]Department of Pathology, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA
          [16 ]Laboratory of Chronic Airway Infection, Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
          [17 ]National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Chapel Hill, NC, USA
          [18 ]Laboratory of Immunology, Shantou University Medical College, Shantou, Guangdong, China
          Author notes
          [19]

          These authors contributed equally.

          [20]

          Lead contact

          Article
          S0092-8674(20)30675-9
          10.1016/j.cell.2020.05.042
          7250779
          © 2020 Elsevier Inc.

          Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Cell biology

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