Influenza viruses infect an estimated 20% of the global population every year and although infection is typically highly acute, influenza viruses can induce prolonged changes to host pulmonary physiology. Due to their importance for global health, influenza viruses are well studied; however relatively little work has been done investigating the fates of infected epithelial cells. This is primarily because the dogma in the field has long held that influenza viruses are exclusively cytopathic viruses, i.e. all infected cells are eventually killed. We were interested in experimentally determining if any cells could survive direct viral infection and potentially continue to affect the host after viral clearance. Using recombinant strains of influenza A virus (IAV) and influenza B virus (IBV), along with transgenic animal systems to monitor the fates of infected cells, we found that up to 3% of the lung epithelium is infected but is not killed by the virus or the subsequent immune response. While the survival of some epithelial cell types was virus specific, both IAV and IBV induced the formation of populations of ?survivor? ciliated cells. Ciliated cells are a terminally differentiated cell type with a well characterized morphology and transcriptional profile, which we hypothesized would be a powerful model to identify and interrogate any long-term effects of viral infection on cellular physiology. We found that viral infection induced a striking loss of the normal ciliated cell identity which not only allowed the expression of genes normally restricted to other epithelial cell types, but also caused morphological and functional changes that were important for the preservation of pulmonary function after infection. In this proposal, we attempt to leverage these observations and experimental models to understand how viruses can affect cellular identity, as well as how cellular identity flexibility relates to viral pathogenesis. The proposed experiments will reveal not only how viral infection can break the normal rules of cellular differentiation, but also reveal a novel host adaptive mechanism to maintain critical organ function during acute viral infection. Long term, the results of this study may also reveal cellular processes that can be therapeutically exploited to improve the outcome of influenza virus infection. !

Public Health Relevance

The identity of the cells infected by influenza viruses has been thought to remain constant over the course of infection. We have recently discovered that some ciliated epithelial cells (which are terminally differentiated), have the ability to survive direct viral infection, and that these ?survivor? cells subsequently experience the loss of their cellular identity. This proposal is designed to study how viral infection can induce cell identity loss in a terminally differentiated cell type and how flexible cellular identity influences influenza virus pathogenesis and pulmonary function. !

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL142985-03
Application #
9969598
Study Section
Virology - A Study Section (VIRA)
Program Officer
Zhou, Guofei
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
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