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Discovery of Novel Signaling Components Targeted by Vibrio


The overall goal of this proposal is to identify novel host signaling components that are targeted during infection of the gut by the gastrointestinal pathogen Vibrio parahaemolyticus. V. parahaemolyticus is a major agent responsible for gastroenteritis outbreaks associated with the consumption of contaminated seafood found in both the Pacific and Atlantic oceans. Understanding how pathogens disrupt normal homeostasis and cripple the host defense response is critical for our understanding of signaling pathways utilized by gastrointestinal cells.<P> Recent sequencing of the V. parahaemolyticus genome has revealed the presence of a pathogenicity island (PAII) that encodes a number of toxins, a type III secretion system (TTSS), one recognizable effector, VopA, and a number of other uncharacterized open reading frames thought to encode novel effectors. Previous studies on effectors demonstrate that these proteins have evolved by capturing or mimicking eukaryotic regulatory functions that are critical for host cell regulation. <P> The discovery of the mechanism utilized by each of these effectors has provided insights into the essential mechanisms of eukaryotic cellular signaling. Our initial studies have focused on the characterization of the effector VopA that belongs to the YopJ-like family of virulence factors. We are using VopA as a representative effector from V. parahaemolyticus to design a system for analysis of unknown effectors encoded within PAII. By identifying the novel virulence factors expressed by V. parahaemolyticus and revealing their targets in a eukaryotic cell, we will uncover new critical components of host signaling pathways. <P> This grant will be used to fund research involved in developing an in vitro V. parahaemolyticus infection system to study pathogenic effectors produced by a gram-negative marine bacterium that is responsible for causing food poisoning worldwide. Results from this application will be used as preliminary data for the submission of a future RO1 application.

Orth, Kim
University of Texas Southwestern Medical Center
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