Individuals aged 65 years or older account for 80-90% of deaths from influenza A virus each year. The overarching goal of this project is to systematically test the hypothesis that modulating mitochondrial function can alter lung repair after influenza A infection. In the first cycle, we generated data in the C. elegans model to suggest that the mild reduction in mitochondrial electron transport capacity during aging promotes proteostasis. To test this hypothesis in a mammalian system, we began to age Ndufs2 heterozygous (Ndufs2+/-) mice. Ndufs2 is a catalytic subunit of complex I of the mitochondrial electron transport chain. Ndufs2 heterozygous mice have a 50% reduction in maximal mitochondrial complex I capacity, but appear normal up to one year of age. In contrast, our preliminary data indicate that complete loss of Ndufs2 in alveolar epithelial cells causes the death of mice at a young age. Interestingly, loss of an accessory subunit of mitochondrial complex I, Ndufs4, which results in ~80% loss of mitochondrial complex I function (hypomorph), does not cause lung pathology at baseline. This has led us to hypothesize that mild reductions in mitochondrial complex I function will improve recovery after influenza A infection, while more severe reductions will induce high levels of ATF4 that will impair lung repair. Our preliminary data also indicate that regulatory T cells (Tregs) are essential for alveolar epithelial cell repair after influenza A virus infection. Tregs from aged mice have increased DNA hypermethylation and are unable to repair influenza A virus-induced lung injury. Thus, we will determine whether partial or complete loss of mitochondrial complex I function in Tregs prevents lung repair after influenza A virus infection. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Does a decline in maximal mitochondrial complex I function (Ndufs2+/- mice) over a lifespan improve recovery from influenza A-induced pneumonia during aging? (2) Is ATF4 activation required for the increase in influenza A-induced lung injury induced by the complete loss or hypomorph of mitochondrial complex I function in alveolar epithelial cells? (3) Is the complete loss or hypomorph of mitochondrial complex I function in regulatory T cells (Tregs) sufficient to dampen their ability to promote tissue repair after lung injury?
It is not required per instructions stated on the Funding Opportunity Announcement PAR-18-297, Section IV. Application and Submission Information, Project, Research & Related Other Project Information (Project), ?Project Narrative: Do not complete?.
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