An aberrant immune-epithelial progenitor niche drives post-viral sequelae 3466

Abstract Description Post-Acute Sequelae of COVID-19 (PASC) are rapidly evolving into a major public health concern. However, the link between acute infection and chronic disease remains unclear. With insights from 3 PASC patient cohorts, we established a clinically relevant mouse model and identified an aberrant immune-epithelial progenitor niche unique to the fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found that lung-resident CD8+ T-cell (TRM)-derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, promoting the accumulation of dysplastic epithelial progenitors to drive fibrosis. Neutralization of IFN-γ and TNF, or IL-1β activity improved alveolar regeneration and pulmonary function, presenting a therapeutic strategy to rescue post-viral disease in the aftermath of infection. We believe that the accumulation of CD8+ TRMs occurs due to an evolutionary need of the epithelium to maintain memory of injury and ensure rapid protection at these vulnerable sites in case of subsequent viral exposures. Dysregulation of this immune-epithelial crosstalk however, results in pathological remodelling of the lungs as observed in PASC. Thus, we are exploring the role of epithelium and the molecular basis of this crosstalk to identify key mediators to ultimately uncouple the protective and pathological functions of CD8+ TRMs post-infection to promote functional lung recovery without compromising immunity to future infections. Funding Sources Harish Narasimhan: F31HL170746 and T32AI007496 Jie Sun: AI147394, AG069264, AI112844, HL170961, AI176171 and AI154598 Topic Categories Viral Immunology (VIR)