Immune-epithelial progenitor interactions drive age-associated dysplastic lung repair post viral pneumonia

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PROJECT SUMMARY/ABSTRACT Respiratory viral infections such as SARS-CoV-2 and influenza are a leading cause of morbidity and mortality, accounting for approximately 2 million deaths per year and an even higher healthcare burden during pandemics. Individuals over the age of 65 in particular, are susceptible to adverse outcomes during acute respiratory illness. In addition to increased severity of acute disease, aged individuals are at higher risk of developing chronic pulmonary sequelae – termed “post-acute sequelae of COVID-19” (PASC) in the context of SARS-CoV-2 infection. Depending on the study criteria, 27-80% of convalescents have been found to develop chronic disease and thus PASC is quickly developing into a major burden on healthcare systems worldwide. Notably, this phenomenon is not only limited to SARS-CoV-2 and has been reported following several other respiratory viral infections including influenza, SARS-CoV-1, MERS, RSV and rhinovirus. Increased susceptibility of aged individuals to chronic pulmonary sequelae and adverse long-term outcomes remains a consistent feature across all viruses. However, we have limited insight into the age-associated features responsible for the development and maintenance of chronic pulmonary sequelae following acute viral injury. Our lab and others have previously reported persistent dysregulation of immune responses following respiratory viral infections during aging. Long-term maintenance of tissue resident CD8+ memory T- (CD8+ TRM) cells was found to contribute to chronic pathology in aged lungs. The molecular mechanisms underlying this pathological activity were previously unknown, but I now present data that CD8+ TRM cells persisting in aged lungs contribute to impaired alveolar regeneration post viral injury. Upon depletion of CD8+ TRM cells in the post-acute phase of infection, I observe a reduction in the long-term maintenance of Krt8+ transitional cells – an intermediate state adopted by alveolar epithelial type 2 (ATII) cells prior to differentiation into ATI cells. Coupled with the observed increase in ATI cells, these data indicate that CD8+ TRM cells impair the complete differentiation of Krt8+ transitional cells into mature ATI cells, thereby compromising pulmonary function. I also found that CD8+ TRM depletion results in reduced IL-1β levels, a cytokine known to regulate Krt8+ transitional cell activity. Thus, my overall hypothesis is that CD8+ TRM cells persisting in aged lungs following viral pneumonia contribute to chronic IL-1β release and thus impair Krt8+ transitional cell differentiation to promote dysplastic lung repair. To address my hypothesis, I propose to 1) determine the contributions of CD8+ TRM cells persisting in aged lungs to impaired alveolar regeneration and 2) elucidate the pathological mechanisms driven by CD8+ TRM cells to promote dysplastic repair of aged lungs. Understanding this immune-epithelial progenitor interaction would deepen our fundamental understanding of the role of the immune system in alveolar regeneration and lung repair. Moreover, the proposed studies would pave the way for developing therapeutic strategies to promote functional repair of aged lungs following severe viral pneumonia.