# Pulmonary Epithelial Dynamics and Innate Host Defense

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $480,973

## Abstract

Project Summary
The RNA virus that causes influenza is inhaled into the airways and binds to terminal sialic acid residues on
host cell surface glycoproteins via viral sialic acid receptors. The tracheitis, bronchitis and bronchiolitis that
results is often accompanied by incapacitating cough, headache, fever and myalgias, but the syndrome usually
resolves in 7-10 days without development of alveolitis. This is fortunate because once the pulmonary
parenchyma is involved, mortality increases almost 60 fold, from 0.3 to 17.8 annual deaths per 100,000(2006
CDC data). Because we believe that infection of alveolar type II (ATII) cells is the pivotal event in the
conversion of a self-limited influenza virus (IV) airway infection to a potentially lethal alveolar infection, our
proposal focuses on the mechanisms that render the ATII cells resistant or susceptible to infection with IV.
Although ATII cells are clearly the primary epithelial target for IV in the alveolus, they are remarkably resistant
to IV infection in their typically quiescent state in the unperturbed lung, in which fewer than 1% of ATII cells are
cycling. Recent in vitro studies have demonstrated that the PI3K/Akt/mTOR pathway, which regulates cellular
proliferation, plays a key role in susceptibility and severity of IV infection by enhancing cell surface binding,
endocytosis, lysosomal acidification driven entry into the cytoplasm, replication using cellular translational
machinery, and anti-apoptotic mechanisms that prolong viral production. Mitogenic stimulation of
PI3K/Akt/mTOR pathway with intrapulmonary keratinocyte growth factor (KGF) converts ATII cells from a
quiescent, IV resistant state to a proliferative, IV susceptible state, and hastens the progression of IV infection
from the conducting airways to the alveolus, markedly accelerating mortality. Our hypothesis is that key host
factors, such as transient hyperoxia, render hosts susceptible to influenza pneumonia (IP) through their impact
on the proliferative tone of the ATII pool. Our goals are to determine the mechanisms of mitogen-induced
susceptibility to influenza A virus susceptibility by completing three specific aims: 1) mechanisms of mitogen-
induced susceptibility of AECII cells to IAV infection, 2) host states that affect IAV susceptibility through
mitogenic effects on AECII cells, 3) genetic models of AECII signaling and anti-proliferative strategies for IAV
prophylaxis and therapy. Successful completion of these aims will reveal the importance of a paradigm-shifting,
AECII-centric host susceptibility mechanism, and suggest novel approaches to influenza prophylaxis and
therapy.

## Key facts

- **NIH application ID:** 9836867
- **Project number:** 5R01HL135122-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Francis Xavier McCormack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,973
- **Award type:** 5
- **Project period:** 2017-12-07 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836867

## Citation

> US National Institutes of Health, RePORTER application 9836867, Pulmonary Epithelial Dynamics and Innate Host Defense (5R01HL135122-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836867. Licensed CC0.

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