1. SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice.
- Author
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Dinnon KH 3rd, Leist SR, Okuda K, Dang H, Fritch EJ, Gully KL, De la Cruz G, Evangelista MD, Asakura T, Gilmore RC, Hawkins P, Nakano S, West A, Schäfer A, Gralinski LE, Everman JL, Sajuthi SP, Zweigart MR, Dong S, McBride J, Cooley MR, Hines JB, Love MK, Groshong SD, VanSchoiack A, Phelan SJ, Liang Y, Hether T, Leon M, Zumwalt RE, Barton LM, Duval EJ, Mukhopadhyay S, Stroberg E, Borczuk A, Thorne LB, Sakthivel MK, Lee YZ, Hagood JS, Mock JR, Seibold MA, O'Neal WK, Montgomery SA, Boucher RC, and Baric RS
- Subjects
- Animals, Antiviral Agents, Fibrosis, Humans, Lung pathology, Mice, SARS-CoV-2, COVID-19 complications
- Abstract
A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
- Published
- 2022
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