SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.
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.
Hou, YJ; Okuda, K; Edwards, CE; Martinez, DR; Asakura, T; Dinnon, KH; Kato, T; Lee, RE; Yount, BL; Mascenik, TM; Chen, G; Olivier, KN; Ghio, A; Tse, LV; Leist, SR; Gralinski, LE; Schäfer, A; Dang, H; Gilmore, R; Nakano, S; Sun, L; Fulcher, ML; Livraghi-Butrico, A; Nicely, NI; Cameron, M; Cameron, C; Kelvin, DJ; de Silva, A; Margolis, DM; Markmann, A; Bartelt, L; Zumwalt, R; Martinez, FJ; Salvatore, SP; Borczuk, A; Tata, PR; Sontake, V; Kimple, A; Jaspers, I; O'Neal, WK; Randell, SH; Boucher, RC; Baric, RS
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