Abstract

Salmonella are prominent intestinal pathogens that cause both enteritis and systematic disease. The overall goal of this unit is to utilize the resources of the Program Project in an interactive approach to elucidate key aspects of Salmonella pathogenesis in the intestinal tract as well as in systemic tissues. Salmonella represents an excellent model for an invasive intestinal pathogenesis in the intestinal tract as well as in systemic tissues. Salmonella represents an excellent model for an invasive intestinal pathogen since the organism is amenable to detailed molecular genetic analysis.
Specific Aim 1 is to identify S. typhimurium genes that are important for infection of human intestinal epithelial cells and stimulation of pro-inflammatory epithelial cell responses. This approach will utilize the expertise of Dr. Kagnoff's laboratory in epithelial cell signaling in response to mucosal infections. Specific mutations in Salmonella genes governing attachment invasion and intracellular growth will be tested for effects on human epithelial cells in culture and examined in vivo using human intestinal xenografts in SCID mice.
Specific Aim 2 is to isolate rpoS-regulated genes in S. typhimurium and determine their virulence phenotypes. This proposal is directly derived from work showing that the alternative sigma factor sigmas (RpoS) is a prominent regulatory element during Salmonella infection of host cells, including intestinal epithelial cells. rpoS-regulated genes will be identified by a molecular genetic approach, and virulence will be tested in mice as well as in models of human intestinal infection.
Specific Aim 3 is to determine the roles of polymorphonuclear leukocytes in a) natural resistance to oral infections by Salmonella of different O antigen types, b) protecting mice that have defective macrophage function (a mutant Nramp 1 allele) from Salmonella infections; and c) acquired immunity (antibody mediated) to Salmonella.
This aim will complement work on the ability of epithelial cells to initiate the pro-inflammatory host response, and will focus on crucial host defenses that limit the spread of infection from the intestine to systemic sites.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK035108-14
Application #
6270615
Study Section
Project Start
1998-04-05
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

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

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