Novel mouse model for studying gut epithelial-cell intrinsic responses to helminth infections

Project Summary Enteric helminth 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), T helper 2 (Th2), and eosinophil 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 previous advancements 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 epithelial cells. This limits effective treatment options to enteric parasitic infections. The goal of this proposal is therefore to generate new tools to study epithelial-cell intrinsic regulation of type-2 immune responses. In aim 1, we will generate an epithelial-cell specific conditional knock-out mouse model using CRISPR/Cas9. In aim 2, we will validate the new mouse model in Nippostrongylus brasiliensis and Heligmosomoides polygyrus helminth infection models. These findings may provide rational approaches to modulate type-2 inflammation to enteric parasite infections in humans.