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

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science
    • Subject Terms:
      COVID-19*/complications; Animals ; Antiviral Agents ; Fibrosis ; Humans ; Lung/pathology ; Mice ; SARS-CoV-2
    • 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.
    • Grant Information:
      P30 CA016058 United States CA NCI NIH HHS; R01 AI110700 United States AI NIAID NIH HHS; R01 HL160046 United States HL NHLBI NIH HHS; T32 AI007419 United States AI NIAID NIH HHS; R01 AI157155 United States AI NIAID NIH HHS; P01 HL107202 United States HL NHLBI NIH HHS; R01 HL135156 United States HL NHLBI NIH HHS; U19 AI142759 United States AI NIAID NIH HHS; R01 HL152077 United States HL NHLBI NIH HHS; U54 CA260543 United States CA NCI NIH HHS; K08 HL129075 United States HL NHLBI NIH HHS; U19 AI171292 United States AI NIAID NIH HHS; R01 HL128439 United States HL NHLBI NIH HHS; P01 HL132821 United States HL NHLBI NIH HHS; P30 DK065988 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Antiviral Agents)
    • Publication Date:
      Date Created: 20220720 Date Completed: 20220930 Latest Revision: 20240510
    • Publication Date:
      20240510
    • Accession Number:
      PMC9273046
    • Accession Number:
      10.1126/scitranslmed.abo5070
    • Accession Number:
      35857635