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.
