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EPG5 was identified as essential for autophagy in a genetic screen in Caenorhabdis elegans.Subsequently, a human disease, called Vici syndrome, characterized by severe malformations of the central nervous system, muscle disease, and recurrent pulmonary infections was discovered to be associated with mutations in EPG5 (Gullup, T., et al.2013, Nat Genet.45(1):83).Consistent with an important role for EPG5 in the nervous system, mice lacking Epg5 develop a progressive neurodegenerative disease (Zhao, H., et al.2013, J Cell Biol 200:731.).However, the role of Epg5 in other organs, in particular the immune and inflammatory system,has not been defined in detail.We found that Epg5-/-mice are highly resistant to infection with the H1N1 influenza virus, as shown by a failure of the virus to induce weight loss, diminished viral replication early after infection, and decreased infection of both pulmonary epithelial and parenchymal cells.Because the effects of Epg5 deficiency on influenza infection occurred within 48 hours of infection, we sought to define innate immune correlates of resistance in uninfected mice.We found that the lungs of Epg5-/-mice showed base-line cellular abnormalities prior to infection including increases in neutrophils, alveolar macrophages, B cells and p62 aggregates in alveolar macrophages.Remarkably, the lungs of Epg5-/-mice exhibited significantly increased mRNAs for a range of inflammatory cytokines including TNFα, IL-1β, IL-6, IL-13 and chemokines, but not IFNβ.By immunofluorescence for IL-13 in lung tissue slides,alveolar macrophages were found to be one source of increased cytokines.Further, Epg5-/-bone marrow-derived macrophages exhibited a significant decrease in autophagy shown by p62 protein increase but not mRNA both in vivo and in tissue culture, confirming the role of Epg5 in autophagy in primary macrophages.These findings are consistent with basal autophagy playing a key role in setting the base-line level of activity of the cellular and cytokine components of the innate immune response.This work was supported by NIH U19 AI109725, R01 084887, and grant 274415 from the Crohn's and Colitis Foundation.