Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Abstract

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear. In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

Macrophages and pulmonary fibrosis: a bibliometric and visual analysis of publications from 1990 to 2023

“…Macrophages secrete pro-inflammatory cytokines such as IL-6, IL-1B, and IL-10, promoting the elimination of pathogens and inducing inflammation. The anti-inflammatory cytokines also stimulate collagen and fibroblast production, which are crucial for tissue repair, but can increase the expression of fibrotic factors, resulting in PF ( 25 – 27 ). TNF: lung macrophages exhibit different functional phenotypes under various stimuli and signals, typically either the classical M1 macrophages or the alternatively activated M2 macrophages, both of which play crucial roles in the pathogenesis of PF.…”