1Recent evidence indicates that viral components of the microbiota can contribute to intestinal 2 homeostasis and protection from local inflammatory or infectious insults. However, host-derived 3 mechanisms that maintain tolerance to the virome remain largely unknown. Here, we use 4 colonization with the model commensal murine norovirus (MNV CR6) to interrogate host-5 directed mechanisms of viral tolerance, and show that STAT1 is a central coordinator of 6 tolerance following CR6 colonization. STAT1 restricts CR6 replication to the intestinal tract, 7 prevents systemic viral-induced tissue damage and disease, and regulates antiviral CD4 + and 8 CD8 + T cell responses. In contrast to systemic viral pathogens that drive T cell mediated 9 immunopathology in STAT1-deficient mice, our data indicates that loss of CD4 + or CD8 + T cells 10 and their associated effector functions has no effect on CR6-induced disease. However, 11 therapeutic administration of an antiviral compound to limit viral replication prevented viral-12 induced tissue damage and death despite ongoing dysregulated antiviral T cell responses. 13Collectively, our data uncouple the requirement for STAT1-mediated regulation of antiviral T cell 14 responses from innate immune-mediated restriction of viral replication that is necessary for 15 intestinal viral tolerance. 16 17 34 antiviral treatment can enhance DSS-induced colonic inflammation in mice 8 , indicating that even 35 in the presence of a complex microbiota, the virome (composed of bacteriophage, endogenous 36 retroviruses, and eukaryotic viruses) contributes to intestinal homeostasis. Supporting the 37 hypothesis that host-encoded mechanisms regulate and tolerate viral colonization, latent or 38 chronic viral infection can be reactivated by helminth infection in a STAT6 and interferon (IFN)g-39 dependent manner 9 . 40 41 3 MNV CR6 (CR6) demonstrates features of a mutualistic host-microbe interaction and is an 42 attractive model to interrogate commensal tolerance to a eukaryotic virus. In addition to 43 providing supportive signals in immunosufficient GF mice 7,10 , this strain can establish persistent 44 colonic infection with continued shedding for at least two months in the absence of any 45 detectable clinical or histopathological signs in wildtype (WT) mice 11 . Once MNV was 46 identified 12 , sentinel screening of animal units across North America and Europe identified its 47 57 an IL-22/STAT1-dependent mechanism limits intestinal epithelial cell (IEC)-intrinsic viral 58 replication and RV-induced intestinal pathology 22 . Following vaccinia virus infection, STAT1 59 supports optimal antiviral CD8 + T cell expansion and survival 23,24 . In contrast, STAT1-deficient 60 mice exhibit increased numbers of both CD4 + and CD8 + T cells in response to infection with 61 LCMV Armstrong, although these cells do not constrain viral replication 25 . Instead, Stat1 -/mice 62 succumb rapidly to CD4 + T cell mediated immunopathology 25 . Indeed, tissue damage caused by 63 dysregulated lymphocyte su...

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