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Abstract
Intrinsic innate immune mechanisms are the first line of defense against pathogens
and exist to control infection autonomously in infected cells. Here, we showed that
autophagy, an intrinsic mechanism that can degrade cytoplasmic components, played
a direct antiviral role against the mammalian viral pathogen vesicular stomatitis
virus (VSV) in the model organism Drosophila. We found that the surface glycoprotein,
VSV-G, was likely the pathogen-associated molecular pattern (PAMP) that initiated
this cell-autonomous response. Once activated, autophagy decreased viral replication,
and repression of autophagy led to increased viral replication and pathogenesis in
cells and animals. Lastly, we showed that the antiviral response was controlled by
the phosphatidylinositol 3-kinase (PI3K)-Akt-signaling pathway, which normally regulates
autophagy in response to nutrient availability. Altogether, these data uncover an
intrinsic antiviral program that links viral recognition to the evolutionarily conserved
nutrient-signaling and autophagy pathways.