We are broadly interested in the mechanisms of influenza A virus induced disease. We have developed a novel in vivo reporter system with which to label cells that become infected. Importantly, these cells continue to express the reporter even if the virus is eventually cleared from the infected cell. Using this system, we have identified a lung epithelial cell type (club cells) that can become infected, and then clear and survive viral infection. In our preliminary data, we have shown that these cells are highly sensitive to interferon stimulation. Surviving cells also have highly up-regulated expression of chemokines, and that specific depletion or removal of these surviving cells positively influences lung repair after virally induced injury. This proposal will test two major questions: 1) Why are club cells uniquely able to survive direct viral infection (Aim 1) and 2) How are surviving cells influencing lung pathology during viral infection (Aim 2).
Aim 1 details experiments designed to understand how club cells are surviving infection by characterizing the nature of the interferon stimulated gene (ISG) response during viral stimulation. We will not only look at the transcriptional and epigenetic factors influencing the increased ISG response, but also define which ISGs are the most important for influencing cellular survival.
Aim 2 proposes to study how surviving cells are contributing to viral pathogenesis. We will genetically manipulate surviving cells in vivo to modulate their ability to secrete immunomodulatory factors. We will also directly neutralize the factors secreted by surviving club cells. This is the first description of cells tha can survive acute influenza virus infection, and the experiments in this proposal will increase our understanding of the mechanisms underlying cell survival as well as how these cells contribute to viral pathogenesis. Not only are these important questions for understanding the basic science of how viruses induce disease, but may also provide the basis of novel therapeutic intervention strategies targeting surviving cell populations.

Public Health Relevance

Influenza A virus is a pathogen that can cause serious human disease and we have identified a previously uncharacterized population of lung cells that are infected, but survive and clear the virus. These cells maintain a highly activated anti-viral state secrete chemokines, and negatively influence lung remodeling. The goal of this proposal is to characterize these cells and their actions, which represent a novel aspect of influenza pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI116509-02
Application #
9188524
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Hauguel, Teresa M
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Heaton, Brook E; Kennedy, Edward M; Dumm, Rebekah E et al. (2017) A CRISPR Activation Screen Identifies a Pan-avian Influenza Virus Inhibitory Host Factor. Cell Rep 20:1503-1512
Hamilton, Jennifer R; Sachs, David; Lim, Jean K et al. (2016) Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity. Proc Natl Acad Sci U S A 113:3861-6