is the causative agent of cholera, an acute dehydrating diarrhea that is epidemic in many developing countries. Extensive in vitro studies have demonstrated that the ability of V. cholerae to colonize and cause disease requires expression of virulence factors during its infection of hosts. However, how V. cholerae controls its gene expression in response to the changes in environmental signals is largely unknown. Therefore we intend to address these questions: how does V. cholerae alter its gene expression to colonize the human intestine from its inter-epidemic reservoir? What genes must be silenced to facilitate bacterial survival in the gut? In what sequence does V. cholerae initiate these genetic controls? Three specific aims are outlined in this proposal to investigate these situations using an animal model. First, we have developed a novel screening method and have used it to identify a set of genes that are expressed m vitro but repressed during V. cholerae early colonization of infant mice. Among them, repression of a type IV pilus synthesis genes is crucial for colonization. We will study why and how this type of genetic regulation is important for V. cholerae pathogenesis. This will allow for a broader sense of how pathogens overcome host defenses to initiate infection. Second, we have developed a genetic tool allowing us to monitor both gene activation and repression at the single-cell level. Using this novel approach, we will shed light on currently little known temporal changes in gene transcription during the V. cholerae infectious process. The regulation of these changes over time may be important for V. cholerae pathogenesis. Thirdly, we will investigate the role quorum sensing plays in the repression of genes late in V. cholerae infection. This regulation might be of key importance because of its ability to coordinate genetic expression in a broad population of cells, thus orchestrating a shift in the infectious process as a whole. This proposal represents a new focus away from research based solely on genetic activation events, and so will provide a more complete picture of V. cholerae pathogenesis. By understanding the complete genetic properties of the infectious process, we can illuminate the underlying factors that enable V. cholerae to survive and cause disease within the human intestines. The ultimate goal of this research is to gain knowledge that will potentially lead to novel treatments of such diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI072479-01
Application #
7188760
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$386,257
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Zhi; Wang, Hui; Zhou, Zhigang et al. (2016) Differential Thiol-Based Switches Jump-Start Vibrio cholerae Pathogenesis. Cell Rep 14:347-54
Katzianer, David S; Wang, Hui; Carey, Ryan M et al. (2015) ""Quorum Non-Sensing"": Social Cheating and Deception in Vibrio cholerae. Appl Environ Microbiol 81:3856-62
Lasaro, Melissa; Liu, Zhi; Bishar, Rima et al. (2014) Escherichia coli isolate for studying colonization of the mouse intestine and its application to two-component signaling knockouts. J Bacteriol 196:1723-32
Rothenbacher, Francesca P; Zhu, Jun (2014) Efficient responses to host and bacterial signals during Vibrio cholerae colonization. Gut Microbes 5:120-8
Stern, Andrew M; Hay, Amanda J; Liu, Zhi et al. (2012) The NorR regulon is critical for Vibrio cholerae resistance to nitric oxide and sustained colonization of the intestines. MBio 3:e00013-12
Wang, Hui; Chen, Shusu; Zhang, Juan et al. (2012) Catalases promote resistance of oxidative stress in Vibrio cholerae. PLoS One 7:e53383
Tsou, Amy M; Liu, Zhi; Cai, Tao et al. (2011) The VarS/VarA two-component system modulates the activity of the Vibrio cholerae quorum-sensing transcriptional regulator HapR. Microbiology 157:1620-8
Liu, Zhi; Yang, Menghua; Peterfreund, Gregory L et al. (2011) Vibrio cholerae anaerobic induction of virulence gene expression is controlled by thiol-based switches of virulence regulator AphB. Proc Natl Acad Sci U S A 108:810-5
Wang, Yunduan; Wang, Hui; Cui, Zhigang et al. (2011) The Prevalence of Functional Quorum-Sensing Systems in Recently Emerged Vibrio cholerae Toxigenic Strains. Environ Microbiol Rep 3:218-222
Xu, Xiao; Stern, Andrew M; Liu, Zhi et al. (2010) Virulence regulator AphB enhances toxR transcription in Vibrio cholerae. BMC Microbiol 10:3

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