Yixuan J. Hou 1 , 19 , Kenichi Okuda 3 , 19 , Caitlin E. Edwards 1 , 19 , David R. Martinez 1 , 19 , Takanori Asakura 3 , Kenneth H. Dinnon III 2 , Takafumi Kato 3 , Rhianna E. Lee 3 , Boyd L. Yount 1 , Teresa M. Mascenik 3 , Gang Chen 3 , Kenneth N. Olivier 16 , Andrew Ghio 17 , Longping V. Tse 1 , Sarah R. Leist 1 , Lisa E. Gralinski 1 , Alexandra Schäfer 1 , Hong Dang 3 , Rodney Gilmore 3 , Satoko Nakano 3 , Ling Sun 3 , M. Leslie Fulcher 3 , Alessandra Livraghi-Butrico 3 , Nathan I. Nicely 4 , Mark Cameron 11 , Cheryl Cameron 12 , David J. Kelvin 10 , 18 , Aravinda de Silva 2 , David M. Margolis 2 , 5 , 6 , Alena Markmann 5 , Luther Bartelt 5 , Ross Zumwalt 13 , Fernando J. Martinez 14 , Steven P. Salvatore 15 , Alain Borczuk 15 , Purushothama R. Tata 9 , Vishwaraj Sontake 9 , Adam Kimple 7 , Ilona Jaspers 8 , Wanda K. O’Neal 3 , Scott H. Randell 3 , Richard C. Boucher 3 , ∗ , Ralph S. Baric 1 , 2 , 20 , ∗
27 May 2020
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.