The effects of cells that survive direct influenza A virus infection on lung repair

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Project Summary/Abstract Influenza A virus (IAV) is an acute, cytopathic virus that infects a range of different cell types, but principally lung epithelial cells. Viral infection causes extensive damage to both the proximal and alveolar airways. Because virus growth is highly cytolytic in cell culture, and the virus is completely eliminated from the host by the adaptive immune system, it has long been believed that no infected cells are able to survive direct IAV infection. A derivative of this assumption is that the virus is incapable of influencing the host after the resolution of viral infection. I recently developed a Cre recombinase-expressing IAV, which allowed me to permanently label every infected cell and follow their fates. With this virus and transgenic reporter mouse lines, I identified a population of epithelial club cells that survived direct and productive viral infection. Not only can these cells eliminate all traces of the virus and survive, but further characterization of these cells revealed that the cells acquire an altered, and generally inflammatory, transcriptional profile after surviving. Specific depletion of these cells enhanced epithelial regeneration, indicating that survivor cells delay lung repair after the resolution of viral infection. The implication of my preliminary data is that IAV infection leads to the generation of a population of transcriptionally reprogrammed survivor cells that have important inhibitory roles in lung repair. To the best of my knowledge, the contribution of survivor cell populations to lung repair has never been studied. In this proposal, I will assay how the strain specificity of IAV influences the numbers of surviving club cells in vivo. I will then define how survivor cells influence uninfected basal/progenitor cell behavior as well as track the fates of survivor club cells during lung repair. I will specifically evaluate the effects of surviving club cells on the repair of both the larger and alveolar epithelium. The proposed work will explore a completely unstudied regulator of lung repair, and may identify novel mechanisms to therapeutically enhance epithelial regeneration after viral infections.