SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice
Kenneth H. Dinnon, Sarah R. Leist, Kenichi Okuda, Hong Dang, Ethan J. Fritch, Kendra L. Gully, Gabriela De la Cruz, Mia D. Evangelista, Takanori Asakura, Rodney C. Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E. Gralinski, Jamie L. Everman, Satria P. Sajuthi, Mark R. Zweigart, Stephanie Dong, Jennifer McBride, Michelle R. Cooley, Jesse B. Hines, Miriya K. Love, Steve D. Groshong, Alison VanSchoiack, Stefan Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E. Zumwalt, Lisa M. Barton, Eric J. Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B. Thorne, Muthu Sakthivel, Yueh Z. Lee, James S. Hagood, Jason R. Mock, Max A. Seibold, Wanda K. O’Neal, Stephanie A. Montgomery, Richard C. Boucher, Ralph S. Baric
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.