Restriction of viral replication, rather than T cell immunopathology, drives lethality in MNV CR6-infected STAT1-deficient mice

Abstract

Abstract Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. Here, we used colonization of C57BL6/J mice with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral regulation, and show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In STAT1-sufficient mice MNV CR6 is asymptomatic and restricted to the colon, despite the persistence of high viral loads. However, in the absence of STAT1 viral replication is disseminated and observed in key innate and adaptive immune populations. STAT1-deficient mice develop dysregulated inflammatory CD8+ and CD4+ T cell responses, which coincide with weight loss and severe necrosis of the spleen and liver. Despite these altered T cell responses which resemble those that mediate lethal immunopathology following other model viral infections of STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. In contrast, therapeutic administration of an antiviral compound limited viral replication, preventing viral-induced tissue damage and death despite ongoing inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa. Unlike other model viral infections, CR6 induces disease in STAT1-deficient mice via uncontrolled viral replication rather than the concomitant development of dysregulated antiviral T cell responses. Research in the Osborne lab is supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Canada Research Chair program and scholarships from the University of British Columbia.