2. Academic Validation
  3. SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice

SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice

  • Sci Transl Med. 2022 Sep 28;14(664):eabo5070. doi: 10.1126/scitranslmed.abo5070.
Kenneth H Dinnon 3rd 1,  Sarah R Leist 2,  Kenichi Okuda 3,  Hong Dang 3,  Ethan J Fritch 1,  Kendra L Gully 2,  Gabriela De la Cruz 4,  Mia D Evangelista 4,  Takanori Asakura 3,  Rodney C Gilmore 3,  Padraig Hawkins 3,  Satoko Nakano 3,  Ande West 2,  Alexandra Schäfer 2,  Lisa E Gralinski 2,  Jamie L Everman 5,  Satria P Sajuthi 5,  Mark R Zweigart 2,  Stephanie Dong 2,  Jennifer McBride 2,  Michelle R Cooley 2,  Jesse B Hines 6,  Miriya K Love 3,  Steve D Groshong 7,  Alison VanSchoiack 8,  Stefan J Phelan 8,  Yan Liang 8,  Tyler Hether 8,  Michael Leon 8,  Ross E Zumwalt 9,  Lisa M Barton 10,  Eric J Duval 10,  Sanjay Mukhopadhyay 11,  Edana Stroberg 10,  Alain Borczuk 12,  Leigh B Thorne 13,  Muthu K Sakthivel 14,  Yueh Z Lee 14 15,  James S Hagood 3 16,  Jason R Mock 3 17,  Max A Seibold 5 18 19,  Wanda K O'Neal 3,  Stephanie A Montgomery 4 13,  Richard C Boucher 3,  Ralph S Baric 1 2 20
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 5 Center for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206, USA.
  • 6 Golden Point Scientific Laboratories, Hoover, AL 35216, USA.
  • 7 Division of Pathology, Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
  • 8 NanoString Technologies, Seattle, WA 98109, USA.
  • 9 Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 10 Office of the Chief Medical Examiner, Oklahoma City, OK 73105, USA.
  • 11 Department of Pathology, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 12 Weill Cornell Medicine, New York, NY 10065, USA.
  • 13 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 14 Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 15 Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 16 Pulmonology Division and Program for Rare and Interstitial Lung Disease, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 17 Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 18 Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
  • 19 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 20 Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
PMID: 35857635 DOI: 10.1126/scitranslmed.abo5070
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.

Figures
Products