# The innate antiviral response in airway epithelium: a cell type-resolved, functional genomics approach

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Beyond its role in conducting the air required for respiration, the airway epithelium plays a critical role in host
defense through its physical and immunological properties. Specialized secretory cells present in the epithelium
secrete airway mucins, which form a viscous hydrogel protecting the epithelial surface, and the coordinated
beating of multiciliated cells propels this surface liquid and trapped foreign material away from the lower airways.
TP63+ airway basal cells serve as the progenitor cell to replenish all other epithelial cell populations. Additional
rare cell types with as-of-yet incompletely defined functions include FOXI1+ ionocytes and POU2F3+ tuft-like
cells. All epithelial cell types constitute a selectively permeable physical barrier by forming cell-cell junctions with
neighboring cells, such that an electrochemical gradient can be maintained across epithelial boundary. Besides
these physical functions, airway epithelial cells participate in both innate and adaptive immune mechanisms
through pathogen sensing, release of cytokines, and crosstalk with immune cells. The type I interferon (IFN-I)
response is a broad-spectrum, first-line innate immune defense against viruses. While traditionally viewed as
relatively uniform across cell types, preliminary data from our lab and collaborators show that IFN-I induces
distinct gene expression programs across airway cell types, hinting at possible functional heterogeneity in the
IFN-I response on a per-cell type basis. However, it is unclear whether these altered gene expression patterns
and associated transcriptional regulators have functional significance in the context of respiratory virus infection.
A diverse group of respiratory viruses infect the airway epithelium, including influenza viruses, rhinoviruses,
“common-cold” coronaviruses, and SARS-CoV-2. These can be important triggers for acute exacerbations of
chronic airway disease states. The proposed project will develop state-of-the-art CRISPRa/i functional genomics
approaches to perturb IFN-induced regulators and effectors of innate immunity in a human, physiologically
relevant model of the human airway epithelium. This will enable precise functional profiling of the IFN-I response
in individual airway epithelial cell types. Altogether, this work will shed light on how the airway epithelium functions
as an integrated unit to mediate host defense against respiratory viruses and strike a balance between effective
host defense and immune homeostasis (using influenza A virus as a clinically relevant model respiratory
pathogen), with the ultimate goal of developing novel host-directed antiviral therapeutic strategies. More
generally, I anticipate the proposed experimental system developed here will be broadly valuable for precise
genetic characterization of other airway disease states and their interaction with respiratory virus infection,
including COPD, cystic fibrosis, and asthma. This project also presents a uni...

## Key facts

- **NIH application ID:** 10996339
- **Project number:** 1F31HL176050-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Alec P Pankow
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996339

## Citation

> US National Institutes of Health, RePORTER application 10996339, The innate antiviral response in airway epithelium: a cell type-resolved, functional genomics approach (1F31HL176050-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996339. Licensed CC0.

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