Intestinal helminth parasites infect billions worldwide. Mammalian hosts mount a Type 2 inflammatory response to infection, which is characterized by immune cell activation and intestinal epithelial cell mucus secretion that lead to worm expulsion but can also cause pathological excess mucus production. Previous work has focused on how host-derived proteins called cytokines control Type 2 inflammation, but other factors such as the lipid prostaglandin D2 (PGD2) are also produced during infection. PGD2 promotes Type 2 allergic lung inflammation by binding to CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). However, how the PGD2-CRTH2 pathway interacts with cytokines to regulate Type 2 inflammation during intestinal helminth infection is unclear. Our preliminary studies revealed that following infection with the helminth Nippostrongylus brasiliensis, CRTH2-deficient mice had decreased Type 2 immune activation compared to controls, but surprisingly also had increased epithelial mucin responses and accelerated worm clearance. This phenotype was also observed in infected bone marrow chimeric mice in which only non- hematopoietic cells lacked CRTH2, suggesting that the PGD2-CRTH2 pathway suppresses intestinal epithelial cell mucus responses. Notably, how PGD2 production is regulated is unclear. The epithelial cell-derived cytokine interleukin (IL)-33, which activates immune cells during helminth infection, elicits PGD2 production from mast cells in vitro. Thus, IL-33 may activate the PGD2-CRTH2 pathway in vivo. Our preliminary studies showed that following IL-33 treatment, CRTH2-deficient mice had impaired population expansion of IL-33- responsive group 2 innate lymphoid cells compared to controls, suggesting that optimal responses to IL-33 in vivo require CRTH2. Together, these data provoke the central hypothesis that during helminth infection, IL-33 activates the PGD2-CRTH2 pathway to balance Type 2 inflammatory responses, expelling worms efficiently while limiting pathology. To test this hypothesis, we propose 2 Specific Aims.
Aim 1 will test if PGD2 acts directly on small intestinal epithelial cells to inhibit mucin production during Type 2 inflammation, dependent on CRTH2, using small intestinal organoid cultures and a new mouse model that allows for deletion of CRTH2 only in intestinal epithelial cells.
Aim 2 will test how IL-33 regulates PGD2 production by mast cells to shape immune responses during Type 2 inflammation, using gain- and loss-of-function experiments, adoptive transfer approaches, and bone marrow chimeric mice coupled with N. brasiliensis infection. These data will support the generation of a new paradigm of helminth-induced Type 2 intestinal inflammation that incorporates the effects of PGD2 and CRTH2, and will inform the development and use of drugs that target the PGD2-CRTH2 pathway to treat diseases associated with Type 2 inflammation.

Public Health Relevance

Intestinal helminth parasites infect billions worldwide and cause significant morbidity. Our studies will test how the lipid prostaglandin D2 and its receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) regulate Type 2 inflammation during intestinal helminth infection. Our results will increase our understanding of the role of lipids in regulating anti-helminth responses and will inform the development of new therapies to treat Type 2 inflammation in the intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI130379-03
Application #
9986377
Study Section
Immunity and Host Defense (IHD)
Program Officer
Rothermel, Annette L
Project Start
2019-09-01
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tait Wojno, Elia D; Beamer, Celine A (2018) Isolation and Identification of Innate Lymphoid Cells (ILCs) for Immunotoxicity Testing. Methods Mol Biol 1803:353-370
Oyesola, Oyebola O; Früh, Simon P; Webb, Lauren M et al. (2018) Cytokines and beyond: Regulation of innate immune responses during helminth infection. Cytokine :