Influenza A virus (IAV) causes a significant burden to human health, with an estimated 20% of the global population infected every year despite vaccination. While influenza disease is generally associated with low mortality, there are more severe manifestations of the disease that are characterized by a pro-inflammatory positive feedback loop known as hypercytokinemia. The mechanisms underlying this disease are poorly understood. To identify virally induced sources of inflammation, we utilized recombinant influenza viruses and transgenic animal systems to monitor the fates of cells that are directly infected by IAV. Using this technology, we identified a population of lung epithelial cells that survived direct infection and persisted in the lung after viral clearance. This was an unexpected discovery, because the dogma in the field has long held that IAV is an exclusively cytopathic virus, i.e. all infected cells are killed. These ?survivor? cells exhibit a highly inflammatory transcriptional profile, and we have shown that they can influence the immunopathology caused by viral infection. How these cells influence viral disease however, has remained unknown. Here, we propose to study three central mechanisms that underlie survivor cell effects on IAV pathogenesis.
In aim 1, we will define a novel anti-viral signaling pathway that allows epithelial club cells to survive direct viral infection.
In aim 2, we will determine how survivor cells maintain expression of inflammatory genes even after the stimulating ligands are removed. And in aim 3, we will study how the presence of survivor cells influences both viral replication kinetics and the resolution of inflammation after viral clearance. The proposed research will reveal not only novel aspects of viral pathogenesis, but also potentially reveal new molecular targets which can be therapeutically exploited to prevent excessive inflammation during IAV or other viral infections.

Public Health Relevance

Influenza A virus (IAV) has been thought to kill all of the cells that it infects. We have recently discovered that some cells have the ability to survive direct viral infection and that these ?survivor? cells are phenotypically altered and influence host recovery from infection. This proposal is designed to study how surviving cell populations are formed, how their behavior is altered by infection, and how they influence the viral disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI137031-03
Application #
10086045
Study Section
Virology - A Study Section (VIRA)
Program Officer
Lane, Mary Chelsea
Project Start
2019-02-01
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
3
Fiscal Year
2021
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