RESEARCH ARTICLE The Epigenetic Regulator G9a Mediates Tolerance to RNA Virus Infection in Drosophila

Little is known about the tolerance mechanisms that reduce the negative effects of microbial infection on host fitness. Here, we demonstrate that the histone H3 lysine 9 methyltransfer-aseG9a regulates tolerance to virus infection by shaping the response of the evolutionary conserved Jak-Stat pathway in Drosophila. G9a-deficient mutants are more sensitive to RNA virus infection and succumb faster to infection than wild-type controls, which was as-sociated with strongly increased Jak-Stat dependent responses, but not with major differ-ences in viral load. Genetic experiments indicate that hyperactivated Jak-Stat responses are associated with early lethality in virus-infected flies. Our results identify an essential epi-genetic mechanism underlying tolerance to virus infection. Author Summary Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune response. The molecular mechanisms under