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

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2024 · $28,764

## Abstract

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 th...

## Key facts

- **NIH application ID:** 10929396
- **Project number:** 5F31HL170746-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Harish Narasimhan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $28,764
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929396

## Citation

> US National Institutes of Health, RePORTER application 10929396, Immune-epithelial progenitor interactions drive age-associated dysplastic lung repair post viral pneumonia (5F31HL170746-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10929396. Licensed CC0.

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