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.

Public Health Relevance

Although the vast majority of the 3-5 million people who develop influenza every year recover after a brief illness, some develop influenza pneumonia, which can result in severe illness or death. Influenza pneumonia is more likely to occur when the virus encounters cells that have been stimulated to grow through lung injury or other process, which we have found reduces their natural resistance to infection. We are looking for ways to limit the spread of influenza from the bronchial tubes to the air sacs of the lung, which will reduce the incidence of pneumonia by restoring the resistance of lung cells lining the air sacs to influenza infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135122-02
Application #
9609491
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Caler, Elisabet V
Project Start
2017-12-07
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Social Sciences
Type
Schools of Public Health
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Nikolaidis, Nikolaos M; Noel, John G; Pitstick, Lori B et al. (2017) Mitogenic stimulation accelerates influenza-induced mortality by increasing susceptibility of alveolar type II cells to infection. Proc Natl Acad Sci U S A 114:E6613-E6622