# Defining mechanisms of CC16 on epithelial-driven host responses to pathogens

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $606,414

## Abstract

Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have
shown that asthma is the most important risk factor for COPD that develops through a course of low lung function
from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic
underlying mechanisms of this progression. In the first cycle of funding, we addressed this gap by focusing on
the role of CC16 in mediating the immune response that yields protection against lung function decline. We
published several key reports providing mechanistic and clinical evidence supporting the notion that persistent
early life infections in the context of CC16 deficits may be a previously overlooked link in understanding
progression of asthma into severe asthma with fixed airflow limitation. Additionally, we identified 2 novel ligands
for CC16’s protective activity in different compartments, a4b1(VLA-4) in the circulation and a2b1 (VLA-2) in the
respiratory tract. By engaging with VLA-4 in circulation on activated leukocytes, CC16 limits cellular migration
into the airways and reduces airway hyperresponsiveness. By engaging with VLA-2 on epithelial cells, CC16
promotes antimicrobial and antiviral secretion thereby aiding in host defense against pathogens.
In this renewal application, we will continue these translational studies and test the overall hypothesis that
CC16 protects against Rhinovirus (RV) infection by promoting epithelial-driven antiviral host responses and that
early life infections in the context of low CC16 leads to epigenetic changes resulting in enhanced airway
remodeling. RV is the most common trigger of asthma exacerbations, especially in severe asthmatics and elicits
acute exacerbations. Since CC16 is known to be lower in asthma patients, we will test the hypothesis that
epithelial-driven antiviral host responses are decreased in asthma patient nasal epithelial cell samples via CC16-
dependent mechanisms and that delivery of rCC16 and CC16-derived peptidomimetics offers a therapeutic
benefit by enhancing antiviral host responses, thereby reducing RV infection, and limiting airway remodeling.
This hypothesis will be tested by pursuing three specific aims: 1) Determine mechanisms by which CC16
promotes epithelial-driven host defense against respiratory pathogens, 2) Examine the impact of CC16
deficiency during early life viral infection on lung development and function in adult life and 3) Determine if
circulating CC16 levels and asthma status impact nasal epithelial cell production of antimicrobials and antivirals
and if exogenous CC16 can augment production in a VLA-2 dependent manner.

## Key facts

- **NIH application ID:** 10996622
- **Project number:** 2R01HL142769-06
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Julie Gunnells Ledford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,414
- **Award type:** 2
- **Project period:** 2019-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996622

## Citation

> US National Institutes of Health, RePORTER application 10996622, Defining mechanisms of CC16 on epithelial-driven host responses to pathogens (2R01HL142769-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10996622. Licensed CC0.

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