Epithelial cells form a physical and biochemical barrier against the vast number of microbes inhabiting the gut. Secretion of mucus and antimicrobial peptides by epithelial cells enhance barrier function and shape the composition of the microbiota. Intestinal epithelial cells also monitor lumenal microbes and transmit information to underlying immune cells to shape mucosal immunity. Within the collective epithelium there are six specialized subsets of cells, including tuft cells. Previously, the function of tuft cells was unknown until our group and two others reported their role in parasite response and mucosal immunity. The mechanistic basis of parasite recognition by tuft cells is poorly understood, as both the receptors and microbial agonists are unknown. To close this knowledge gap, this proposal will build on our observation that tuft cells utilize taste-chemosensation to respond to parasite infections. First, we will identify the taste-chemosensory receptors that detect parasites. In parallel we determine the microbial agonists that stimulate tuft cell taste chemosensation. Using next-generation sequencing and gnotobiotic mice, this study will disentangle the role of the parasite-altered microbiome from direct stimulation of tuft cells by parasites and their products. This project will yield valuable information on specific interactions between tuft cell receptors and their agonists thereby expanding the understanding of taste receptors as novel intestinal microbial recognition receptors. Tuft cells and taste-chemosensation are fundamentally new form of microbial detection in the gut and represent a promising area to develop future therapies targeting intestinal inflammatory disease. In addition the data, training, and knowledge obtained from this proposal are critical for my continued development as an independent investigator.

Public Health Relevance

Intestinal tuft cells are an epithelial cell type that detect parasites and orchestrate mucosal immunity. This proposal examines the microbial signals and tuft cell receptors that enable parasite detection. A better understanding of the relationship between tuft cells, parasites, and the immune system will ultimately uncover new strategies to treat intestinal inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK113041-03
Application #
9674463
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2017-04-05
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Haber, Adam L; Biton, Moshe; Rogel, Noga et al. (2017) A single-cell survey of the small intestinal epithelium. Nature 551:333-339