A gut commensal protist protects against virus-mediated loss of oral tolerance

Abstract

Abstract Loss of oral tolerance (LOT) to gluten, characterized by a T helper 1 (Th1) gluten-specific immune response, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. We hypothesized that certain gut microbes have the capacity to protect against virus-mediated LOT. By using our previously defined reovirus-mediated LOT CeD model, we discovered that the gut colonizing protist Tritrichomonas promotes oral tolerance and protects against reovirus-mediated LOT by suppressing the reovirus-induced proinflammatory program of dietary-antigen-presenting CD103+ dendritic cells. Importantly, Tritrichomonas-mediated protection against T1L-induced LOT is not attributable to differences in antiviral host responses and is independent of the microbiota. Mechanistically, we show that Tritrichomonas colonization restrains reovirus-induced inflammatory responses in dendritic cells and thus limit their ability to promote Th1 immune responses. Finally, our studies using human stool samples support a role for Tritrichomonas sp. colonization in protecting against development of CeD. Supported by grants from NIH (T32 AI089443)