Elucidating an immune epithelial niche underlying post viral lung fibrosis

About This Grant

Project Summary Respiratory viruses can acutely lead to high mortality from respiratory failure. However, respiratory viral infections also cause permanent morbidity long after recovery from the acute infection. Such chronic debilitation was best exemplified during the COVID-19 pandemic that left many patients with post-acute sequelae of SARS-CoV-2 (PASC; aka long COVID). One unfortunate consequence after a severe COVID-19 infection is the development of persistent pulmonary fibrosis (PASC-PF). However, this fibrotic remodeling of the lungs is not unique to infections by SARS-CoV-2 and has also been found with other viral infections such as influenza, MERS-CoV, SARS-CoV-1. Investigations into PASC-PF have revealed common features when compared to idiopathic pulmonary fibrosis (IPF), the archetype of progressive lung fibrosis. A fundamental feature in PASC-PF, IPF, and other types of lung fibrosis is the maladaptive repair of the lung epithelium that is an upstream driver of fibroproliferation. In particular, the type 2 alveolar epithelial cell (AT2) cells, which are the facultative epithelial stem cells of the alveoli, are exhausted and fail to properly repair the lungs after injury. Accordingly, damaged alveoli have a repair deficiency with a failure of AT2 differentiation into alveolar type 1 (AT1) cells that are necessary for lining the alveoli to facilitate gas exchange in the lungs. To that end, recent studies have found IFN-γ to be a key signaling node that is enriched in PASC-PF and IPF. Moreover, studies by our group and others have demonstrated IFN-γ blockade to reduce fibrosis and augment epithelial repair in a viral-induced lung fibrosis model. Accordingly, we have developed a central hypothesis that anti-viral immunity by CD8+ T cells directly (via IFN-γ) and indirectly (via MDM secretion of IL-1β) stalls alveolar regeneration thereby shifting the injury response toward maladaptive repair thereby activating fibroproliferative pathways. We will test the hypothesis in three aims: Aim 1. Evaluate viral-mediated maladaptive reprogramming of AT2 cell. Aim 2. Uncover the cellular and molecular mechanisms that mediate the abnormal immune-epithelial interactions contributing to chronic lung fibrosis following viral infection. Aim 3. Identify abnormal immune-epithelial interactions in human post-viral lung fibrosis . The successful completion of this study promises to elucidate the cellular and molecular etiology of lung fibrosis and have a broad impact on understanding fibroproliferative mechanisms in PASC-PF, IPF, and other forms of lung fibrosis.