SARS-CoV-2 infection produces an IL-33-dependent chronic eosinophilic pneumonia and muco-inflammatory airways disease in Scnn1b-Tg mice.

Post-acute sequelae of SARS-CoV-2 (PASC) occurs in subsets of individuals, including those with preexisting lung disease. To investigate PASC pathogenesis and therapeutics in a chronic bronchitis mouse model (Scnn1b-Tg), Scnn1b-Tg and WT mice were inoculated with a mouse-adapted SARS-CoV-2 virus (SARS-CoV-2 MA10) and followed for 60 days. Viral titer, histology, immunohistochemistry, single-cell RNA sequencing, RNA in situ hybridization, and spatial transcriptomic profiling characterized disease pathologies. Scnn1b-Tg mice inoculated with SARS-CoV-2 MA10 exhibited lower viral titers and less weight loss than WT mice. Airway epithelia of Scnn1b-Tg mice were less infected than epithelia of WT mice, reflecting increased airway mucus and enhanced epithelial antiviral activities in Scnn1b-Tg mice. However, Scnn1b-Tg mice subsequently exhibited heterogeneous airway and parenchymal disease with elevated Il33 expression characteristic of human eosinophilic pneumonia. Cohorts of infected mice were given a monoclonal antibody targeting the IL-33 receptor (ST2) or enteral prednisone. Administration of an anti-ST2 monoclonal antibody mitigated development of eosinophilic pneumonia, while enteral prednisone suppressed IL-33 expression and disease. The eosinophilic pneumonia in Scnn1b-Tg mice after SARS-CoV-2 MA10 infection mimics reports of eosinophilic pneumonia in humans after SARS-CoV-2, suggesting that targeting of IL-33 may be beneficial in treating post-viral eosinophilic pneumonia in humans.