The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.

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Gammaherpesviruses are important pathogens whose lifelong survival in the host depends critically on their capacity to establish and reactivate from latency, processes regulated by both viral genes and the host immune response. Previous work has demonstrated that gamma interferon (IFN-␥) is a key regulator of chronic infection with murine gammaherpesvirus 68 (␥HV68), a virus that establishes latent infection in B lymphocytes, macrophages, and dendritic cells. In mice deficient in IFN-␥ or the IFN-␥ receptor, ␥HV68 gene expression is altered during chronic infection, and peritoneal cells explanted from these mice reactivate more efficiently ex vivo than cells derived from wild-type mice. Furthermore, treatment with IFN-␥ inhibits reactivation of ␥HV68 from latently infected wild-type peritoneal cells, and depletion of IFN-␥ from wild-type mice increases the efficiency of reactivation of explanted peritoneal cells. These profound effects of IFN-␥ on chronic ␥HV68 latency and reactivation raise the question of which cells respond to IFN-␥ to control chronic ␥HV68 infection. Here, we show that IFN-␥ inhibited reactivation of peritoneal cells and spleen cells harvested from mice lacking B lymphocytes, but not wild-type spleen cells, suggesting that IFN-␥ may inhibit reactivation in a cell type-specific manner. To directly test this hypothesis, we expressed the diphtheria toxin receptor specifically on either B lymphocytes or macrophages and used diphtheria toxin treatment to deplete these specific cells in vivo and in vitro after establishing latency. We demonstrate that macrophages, but not B cells, are responsive to IFN-␥-mediated suppression of ␥HV68 reactivation. These data indicate that the regulation of gammaherpesvirus latency by IFN-␥ is cell type specific and raise the possibility that cell type-specific immune deficiency may alter latency in distinct and important ways.

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6Chigh monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI.

Cytokines regulate viral gene expression with important consequences for viral replication and pathogenesis. Gamma interferon (IFN-␥) is a key regulator of chronic murine gammaherpesvirus 68 (␥HV68) infection and a potent inhibitor of ␥HV68 reactivation from latency. Macrophages are the cell type that is responsive to the IFN-␥-mediated control of ␥HV68 reactivation; however, the molecular mechanism of this IFN-␥ action is undefined. Here we report that IFN-␥ inhibits lytic replication of ␥HV68 in primary bone marrow-derived macrophages and decreases transcript levels for the essential lytic switch gene 50. Interestingly, IFN-␥ suppresses the activity of the two known gene 50 promoters, demonstrating that an inflammatory cytokine can directly regulate the promoters for the ␥HV68 lytic switch gene. Stat1, but not IFN-␣/␤ signaling, is required for IFN-␥ action. Moreover, Stat1 deficiency increases basal ␥HV68 replication, gene 50 expression, and promoter activity. Together, these data identify IFN-␥ and Stat1 as being negative regulators of the ␥HV68 lytic cycle and raise the possibility that ␥HV68 maintains IFN-␥/Stat1-responsive gene 50 promoters to facilitate cell-extrinsic control over the interchange between the lytic and latent cycles.Herpesviruses establish acute lytic infection followed by lifelong, chronic latent infection. The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with tumorigenesis in immunocompromised patients. EBV and KSHV exhibit a strict species specificity, and murine gammaherpesvirus 68 (␥HV68) provides a small-animal model to study gammaherpesvirus infection. ␥HV68 shares sequence homology and genomic organization with EBV and KSHV (60), and ␥HV68 infection is associated with lymphomas and lymphoproliferative disease in immunocompromised mice (25,55,58