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Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19 (preprint)
biorxiv; 2023.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2023.09.13.557622
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-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} 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.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Main subject:
Pneumonia, Viral
/
Pulmonary Fibrosis
/
Respiratory Tract Infections
/
Acute Disease
/
Neoplasms, Glandular and Epithelial
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Adenocarcinoma, Bronchiolo-Alveolar
/
Idiopathic Pulmonary Fibrosis
/
COVID-19
/
Inflammation
Language:
English
Year:
2023
Document Type:
Preprint
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