BACKGROUND: Enteric viral infections have been implied in loss of oral tolerance (LOT) to dietary antigens. We recently showed that reovirus infection in mice suppresses development of regulatory T cells (pTreg) and promotes T helper 1 immunity (TH1) against dietary antigens in a type I IFN and an IRF1-dependent manner, respectively. Eventually, the infection leads to LOT to dietary antigens and was implied in development of celiac disease. To undestand this type I IFN and IRF1-mediated LOT upon enteric viral infection, we investigated the mouse model of norovirus, which causes the majority of epidemic gastroenteritis worldwide.
METHODS: We studied murine norovirus (MNV) in comparion to reovirus to understand the common nature of virus-induced LOT and the role of viral persistence and tissue tropism in LOT. Mice received ovalbumin (OVA) specific TCR (OTII) CD4+ T cells, were infected with MNV and fed with OVA, and then dendritic cells (DCs) and T cells from the mesenteric lymph nodes were analyzed for pTreg and TH1 responses to OVA. OVA-specific antibody responses were also examined in the same context.
RESULTS: MNV indeed broke the oral tolerance to dietary antigens; infection with MNV suppressed the conversion of OT-II CD4+ T cells into pTreg and induced a TH1 response. Like the reovirus infection, induction of the TH1 response against OVA was dependent on IRF1. MNV infected and activated DCs essential for oral tolerance, resulting in production of the proinflammatory cytokine IL-12. Intriguingly, similar to the strain-dependent induction of LOT by reoviruses, an acute strain but not a persistent strain of MNV caused LOT against OVA.
CONCLUSIONS: These data demonstrate that an enteric virus with a different life cycle from that of reovirus is able to trigger inflammatory immune responses to dietary antigens through a similar mechanism, suggesting a common and shared mechanism of viral infection-mediated LOT.