Enteropathogenic E. coli (EPEC), an important food-borne pathogen, causes infantile diarrhea resulting in significant morbidity and mortality. However, the mechanisms of EPEC-induced diarrhea remain unclear. Diarrhea results from either increased secretion, decreased absorption, or both. Earlier studies have failed to conclusively show an increase in host secretory response by EPEC infection. Our preliminary data utilizing Caco-2 cells, showed that EPEC infection significantly inhibited the activities of both the predominant Na+ absorbing isoform NHE3, the CI-OH exchanger and butyrate uptake. An analysis of the EPEC effects on NHEs showed that NHE1 and NHE2 activities were rapidly increased while the activity of NHE3 was significantly decreased. We hypothesize that one of the potential mechanisms of EPEC-induced diarrhea involves a decrease in intestinal absorptive processes. Our proposed studies will explore the effects of EPEC infection on intestinal NHE activities both in in vitro and an in vivo model and elucidate the mechanisms(s) underlying the differential regulation of NHEs by EPEC.
Our Specific Aims are designed to: 1. To dissect the effects of EPEC on NHE isoform activities and Na+ flux in model human small intestinal (Caco-2.bbe) and non-transformed colonic (NCM460) epithelia;2. Define mechanisms of EPEC-induced modulation of NHE isoform activities by elucidating signaling pathways involved, the role of regulatory factors (NHERF1 and NHERF2), the role of the cytoskeletal protein ezrin, and NHE membrane trafficking;3. Examine the effects of EPEC on Na+ transport in ileum and colon in murine model of EPEC infection and in NHE2 &3 knockout mice by determining the expression and activities of NHEs, transepithelial Na+ fluxes, gut luminal fluid accumulation, and the role of EPEC virulence genes. The results of these studies will enhance our understanding of the mechanisms of regulation of human intestinal NHEs and their modulation by pathogenic organisms. Our findings may aid in the future development of improved therapeutic modalities for infectious diarrhea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK067887-05
Application #
8117204
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$203,031
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Choi, Vivian M; Herrou, Julien; Hecht, Aaron L et al. (2016) Activation of Bacteroides fragilis toxin by a novel bacterial protease contributes to anaerobic sepsis in mice. Nat Med 22:563-7
Setty, Mala; Discepolo, Valentina; Abadie, Valérie et al. (2015) Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease. Gastroenterology 149:681-91.e10
Edelblum, Karen L; Singh, Gurminder; Odenwald, Matthew A et al. (2015) ?? Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology 148:1417-26
Sideri, Aristea; Stavrakis, Dimitris; Bowe, Collin et al. (2015) Effects of obesity on severity of colitis and cytokine expression in mouse mesenteric fat. Potential role of adiponectin receptor 1. Am J Physiol Gastrointest Liver Physiol 308:G591-604
Luther, Jay; Garber, John J; Khalili, Hamed et al. (2015) Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability. Cell Mol Gastroenterol Hepatol 1:222-232
Battle, Scott E; Brady, Michael J; Vanaja, Sivapriya Kailasan et al. (2014) Actin pedestal formation by enterohemorrhagic Escherichia coli enhances bacterial host cell attachment and concomitant type III translocation. Infect Immun 82:3713-22
Glotfelty, Lila G; Zahs, Anita; Hodges, Kimberley et al. (2014) Enteropathogenic E. coli effectors EspG1/G2 disrupt microtubules, contribute to tight junction perturbation and inhibit restoration. Cell Microbiol 16:1767-83
Glotfelty, Lila G; Zahs, Anita; Iancu, Catalin et al. (2014) Microtubules are required for efficient epithelial tight junction homeostasis and restoration. Am J Physiol Cell Physiol 307:C245-54
Nalle, Sam C; Kwak, H Aimee; Edelblum, Karen L et al. (2014) Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med 6:243ra87
Ma, Ke; Malhotra, Pooja; Soni, Vinay et al. (2014) Overactivation of intestinal SREBP2 in mice increases serum cholesterol. PLoS One 9:e84221

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