# Gut mucosal type-2 immunity to parasitic infections

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $237,600

## Abstract

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.

## Key facts

- **NIH application ID:** 10415214
- **Project number:** 5R21AI163721-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Reinhard Hinterleitner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,600
- **Award type:** 5
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415214

## Citation

> US National Institutes of Health, RePORTER application 10415214, Gut mucosal type-2 immunity to parasitic infections (5R21AI163721-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10415214. Licensed CC0.

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