Abstract

Giardia lamblia is a major cause of diarrheal disease worldwide, yet little is known of its mechanisms of pathogenesis. Trophozoites are not known to invade, express any virulence factor, or elicit an inflammatory response. Therefore, it is crucial to understand giardial interactions with the intestinal epithelium from both the parasite and the host perspective. The overall goal of this Unit is to elucidate the molecular, cellular, and biochemical cross talk between giardial trophozoites and human intestinal epithelial cells in vitro and in a human intestinal xenograft model. The underlying hypothesis is that physiologic stimuli from host epithelial cells may modulate giardial behavior and enable trophozoites to better colonize and evade natural host defenses. Conversely, attachment of trophozoites may elicit physiologically relevant responses to the host epithelial barrier. We will determine whether the cross talk is due to giardial attachment to live cells or caused by factors released into the environment.
Aim 1 is to investigate trophozoite survival., growth, and attachment responses to cultured human intestinal epithelial cells.
Aim 2 is to test the hypothesis that exposure to epithelial cells or signals from them may: A. cause encysting trophozoites to revert from differentiation to growth; B. change overall trophozoite development programs as manifested by alterations in protein, protein phosphorylation, and mRNA fingerprints; C. induce expression of giardial virulence factors.
Aim 3 is to test the hypothesis that attachment will induce changes in the cytoskeleton and ultrastructure of both trophozoites and intestinal epithelial cells that may give key insights into their interactions.
Aim 4 is to evaluate the human intestinal xenograft model as a system to study the response of normal intestinal epithelial cells to giardial colonization. This system will allow us to define both host and parasite factors required for infection. These studies will greatly extend our understanding of an important intestinal parasite and have the potential to yield new insights into intestinal barrier and defense functions.

  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 #
5P01DK035108-15
Application #
6296428
Study Section
Project Start
1999-04-01
Project End
2000-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
15
Fiscal Year
1999
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

Showing the most recent 10 out of 252 publications