# Modulation of Lung Immune Responses to Viral Infection

> **NIH NIH U19** · JACKSON LABORATORY · 2024 · $2,637,774

## Abstract

PROJECT SUMMARY OVERALL
The main objective of our U19 proposal is to define the contribution of airway epithelial cells to age-related
dysfunction of the tissue-resident immune system, particularly in the context of lung responses to viral infections.
Indeed, age is a major risk factor for increased susceptibility to infectious diseases, including severe seasonal
influenza virus infection. Recently, this risk was brought into even greater focus by the COVID-19 pandemic, with
poor outcomes disproportionately affecting individuals over 65 years of age. While it is well documented that
aging impacts both innate and adaptive immunity, the mechanisms underlying these effects, especially in lung
tissue, are not well understood. In addition, little is known about how the aged airway epithelium contributes to
functional immune alterations during respiratory virus infections. Based on our preliminary studies, we
hypothesize that age-related epithelial changes contribute to chronic inflammation and altered tissue-
resident lung immunity. This hypothesis directly builds upon our current U19 lung immunity research program
that is advancing the concept that the lung epithelium, as the first site of respiratory virus infection and replication,
acts as a critical pathogen barrier both as a modulator and an effector of the immune system. The workhorses
of our program are primary human ex vivo air-liquid-interface (ALI) cultures, derived from airway epithelial
progenitors, which closely resemble in vivo airway epithelial cell composition and responses to viruses. ALI
cultures allow for 1) modelling, in time and space, of interactions between airway epithelium, pathogenic viruses
(influenza and SARS-CoV-2), and immune cells; 2) genetically altering ALI genomes to study specific
genes/pathways; 3) measuring the magnitude and kinetics of transcriptional responses to inflammatory insults
that are difficult to measure in vivo; and 4) studying epigenetic regulation, RNA splicing, and impact of the
microbiome in immune responses. Our findings will be validated using precision tissue slice assays from
uninvolved lung tissue. We will also continue increasing the complexity of our 3D lung models, by incorporating
alveolar space, integrating immune cells, and leveraging 3D bioprinting. To achieve our objective, we structured
our Center around: two integrated research Projects focused on epigenetic, transcriptional, and alternative
splicing mechanisms that we propose lead to a skewed isoform repertoire in aging lung epithelial cells and
dysfunctional tissue-resident immunity; a Technology Development Project that will create sophisticated cellular
models and gene editing tools to support research Project objectives; a Sample Core for storage and distribution
of human tissues; and a Data Science Core for integrative analysis and data dissemination. The Center brings
together clinicians and experts in lung immunology, bioengineering, genomics, and computational biology to
maxi...

## Key facts

- **NIH application ID:** 10824102
- **Project number:** 2U19AI142733-06
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Adolfo Garcia-Sastre
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,637,774
- **Award type:** 2
- **Project period:** 2019-03-05 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824102

## Citation

> US National Institutes of Health, RePORTER application 10824102, Modulation of Lung Immune Responses to Viral Infection (2U19AI142733-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10824102. Licensed CC0.

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