The central theme of the Program Project Is focused on mechanisms that determine innate and acquired immune responses in the intestinal mucosa to enteric microbes and microbial products, and the consequent mucosal protective immune and inflammatory responses. The four interrelated research projects specifically address the regulation of communication between epithelial cells and dendritic cells, and between dendritic cells and T cells, which takes place during mucosal homeostasis and protective immunity. Model enteric pathogens are used to probe mucosal cellular responses in novel in vivo and in vitro murine model systems. The program brings together experienced investigators from the Departments of Medicine, Pathology, and Neurosciences and the UCSD campus based La Jolla Institute for Allergy and Immunology. The investigators have a record of significant expertise in cellular and molecular mucosal immunology, mucosal inflammation, cell signaling and microbial pathogenesis, and a record of collaborative interactions. Research Unit 1 investigates the regulation of innate mucosal immune responses by dendritic cells (DC) and epithelial cells in the colon and small intestine. Unit 1 uses an attaching and effacing lesion-inducing enteric pathogen and rotavirus to probe the host response, and the mechanisms by which granulocyte-macrophage colony stimulating factor determines the outcome of enteric infection. Research Unit 2 investigates intestinal mucosal responses that determine immune defenses against minimally invasive enteric pathogens, using Giardia as a model protozoan pathogen that elicits strong protective immunity in the absence of mucosal inflammation. Research Unit 3 investigates how mucosal adjuvants override the tolerance-inducing effects of T regulatory cells and provoke effector T cell immune responses, with a focus on cholera toxin and Th17 differentiation in vitro and in vivo. Research Unit 4, which is new to the Program with the renewal application, investigates mechanisms by which retinoids determine the balance between normal mucosal homeostasis and protective immunity through their activity on DC and T cells. The research projects are supported by four Cores: a Mouse Model Core, a Histopathology Core, an Imaging and Cell Sorting Core and an Administrative Core.

Public Health Relevance

The intestinal mucosa is a major site of interaction between the host and enteric enteric pathogens that cause diarrheal illness, morbidity and death among millions worldwide each year. These studies will elucidate mechanisms and pathways that determine the host responses to infection with enteric microbes and microbial products. We anticipate our research will result in the identification of cellular and molecular targets that can be used and manipulated to achieve more effective host protective immunity to enteric infections through pharmacological, molecular, cellular and vaccine interventions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (M1))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2017) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut 66:1584-1596
Lakhdari, Omar; McAllister, Christopher S; Wang, Michael et al. (2016) TLR3 signaling is downregulated by a MAVS isoform in epithelial cells. Cell Immunol 310:205-210
de Jong, Petrus R; Taniguchi, Koji; Harris, Alexandra R et al. (2016) ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nat Commun 7:11551
Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina et al. (2016) Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules. J Leukoc Biol 99:475-82
Wang, Kepeng; Karin, Michael (2015) The IL-23 to IL-17 cascade inflammation-related cancers. Clin Exp Rheumatol 33:S87-90
Dann, Sara M; Manthey, Carolin F; Le, Christine et al. (2015) IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia. Exp Parasitol 156:68-78
Bertin, S; Lozano-Ruiz, B; Bachiller, V et al. (2015) Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice. Mucosal Immunol 8:505-15
de Jong, P R; Takahashi, N; Peiris, M et al. (2015) TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP. Mucosal Immunol 8:491-504
Vicente-Suarez, I; Larange, A; Reardon, C et al. (2015) Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol 8:141-51
de Jong, Petrus R; Takahashi, Naoki; Harris, Alexandra R et al. (2014) Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis. J Clin Invest 124:3793-806

Showing the most recent 10 out of 252 publications