Enteropathogenic E. coli (EPEC), an intestinal pathogen that causes diarrhea, is responsible for significant morbidity and mortality, especially among children below 5 years of age in developing countries. The precise mechanism(s) by which EPEC causes diarrhea is currently not known. The bacteria elaborate a syringe-like type III secretion system that delivers key virulence factors directly into host intestinal epithelial cells. During the initial phase of infection, EPEC appears to specifically limit the death of the underlying epithelial cells. The focus of this proposal is the suppression of host cell death by the type III-secreted protein EspZ, which is unique to EPEC and related pathogens. Strains lacking EspZ are highly impaired for colonization and disease in animal models of infection. We hypothesize that EspZ interacts with host proteins to suppress premature death of infected enterocytes and, thereby, plays a key role in intestinal colonization by A/E pathogens. We propose to (1) validate the interaction of EspZ with host cell partners, define EspZ interaction domains, and generate specific EspZ mutants deficient for interaction(s), (2) characterize the role of EspZ and its interaction partners in activating signaling pathways that contribute to the survival of host cells, and (3) define the role of EspZ and its interaction partners in pathogenesis using animal models of infection. Understanding the key role of EspZ, and of host survival to pathogenesis, could lead to future efforts to inhibit EspZ function, and thereby control EPEC-associated diarrhea.

Public Health Relevance

Enteropathogenic Escherichia coli is a diarrhea-causing organism responsible for significant morbidity and mortality in children. This proposal explores the role of host cell survival in Enteropathogenic Escherichia coli colonization and pathogenesis. The eventual goal is to define the critical processes in pathogenesis that can subsequently be targeted for therapeutic purposes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Baqar, Shahida
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University of Arizona
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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Roxas, Jennifer Lising; Viswanathan, V K (2018) Modulation of Intestinal Paracellular Transport by Bacterial Pathogens. Compr Physiol 8:823-842
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Wilbur, John Scott; Byrd, Wyatt; Ramamurthy, Shylaja et al. (2015) The secreted effector protein EspZ is essential for virulence of rabbit enteropathogenic Escherichia coli. Infect Immun 83:1139-49
Roxas, Jennifer Lising; Ryan, Katheryn; Vedantam, Gayatri et al. (2014) Enteropathogenic Escherichia coli dynamically regulates EGFR signaling in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 307:G374-80
Roxas, Jennifer Lising; Wilbur, John Scott; Zhang, Xiangfeng et al. (2012) The enteropathogenic Escherichia coli-secreted protein EspZ inhibits host cell apoptosis. Infect Immun 80:3850-7
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