Exploring the impact of acute lung hypoxia on CD8 T cell phenotypes following severe influenza infection 3979

Abstract Description Lung hypoxia and hypoxemia are features of severe, acute respiratory illnesses. While systemic hypoxemia is a feature of severe influenza infection, the impact of tissue level hypoxia on lung damage and repair during an infection have not been explored. Previously, our laboratory discovered a pathogenic role for the versicanase ADAM Metallopeptidase with Thrombospondin Type 1 Motif 4 (ADAMTS4) in influenza. ADAMTS4 KO mice have reduced hypoxemia and lung damage compared to WT littermates. Using ADAMTS4 KO mice as a model for reduced viral-induced lung damage during influenza, we found an approximately 25% reduction in HIF1a accumulation in CD8 T cells from the lungs of ADAMTS4 KO mice compared to WT mice, suggesting lower levels of cellular hypoxia. This effect is even more pronounced in effector and resident memory CD8 T cells. Using a mouse line with a tamoxifen-inducible, oxygen dependent cre, hypoxic cells during acute influenza infection will be permanently labelled for immunophenotypic assessment during the convalescent period of disease (14-21 days post-infection) to examine how acute hypoxia impacts CD8 T cell phenotype during recovery. We expect that formerly hypoxic CD8 T cells and their progeny will impede proper lung repair and contribute to persistent inflammation following severe influenza infection. Funding Sources CIVIC GR-0002423 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)