Gut mucosal type-2 immunity to parasitic infections

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Project Summary Enteric helminth and protist infections remain a significant global health problem. Although infections by these parasites are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anemia and malnourishment. Infections are strongly associated with protective type-2 immune mediated intestinal inflammation, observed across species, including mice and humans, and characterized by innate lymphoid cell (ILC2), eosinophil, and mast cell recruitment and tissue injury. Mouse models of infection with intestinal parasites have been established to study the cellular and molecular mechanisms of type-2 immune responses in greater detail: Helminths, such as Nippostrongylus brasiliensis and Heligmosomoides polygyrus, and certain protists of the order Trichomonadida induce acute host type-2 immune defense responses in the small intestine upon infection. Type-2 immune responses are initiated by parasite sensing interleukin-25 (IL-25) producing epithelial tuft cells, resulting in the activation of IL-13 producing ILC2 that in turn signal back on epithelial cells. This feedforward IL-25-ILC2-IL-13 circuit amplifies type-2 immune responses and initiates massive tissue remodeling including tuft- and goblet cell hyperplasia, and mucus production resulting in the containment of intestinal parasites. Despite the recent advancement in our understanding in immune-tissue crosstalk in type-2 mediated inflammation, we lack a complete understanding of the detailed processes underlying parasite-induced type-2 immune responses in the gut; these limits effective treatment options to enteric parasitic infections. To characterize type-2 mediated inflammation in the intestine in greater detail we screened for novel players implicated in intestinal type-2 inflammation. We identified a set of highly homologous genes that were significantly upregulated in the intestine upon type-2 inducing parasitic infections in vivo and in small intestinal organoid cultures upon IL-13 stimulating conditions in vitro. The goal of this proposal is therefore to study the role of these newly identified type-2 inducible genes in the protective type-2 immunity to protists and helminths and their function in intestinal epithelial cells. We generated knock-out mice and use a retroviral expression system in small intestinal organoid cultures. In aim 1, we will study the role of these candidate genes in host type-2 immune responses to protists and helminths in vivo and in aim 2 we will assess their function in intestinal epithelial cells under type-2 immune stimulating conditions in vitro. These findings may provide rational approaches to modulate type-2 inflammation to enteric parasite infections in humans.