Vibrio cholerae is a facultative human pathogen that causes the severe diarrheal disease cholera. The ability of V. cholerae to cause disease is dependent upon the regulated expression of virulence factors. For example, the virulence genes encoding for production of cholera toxin and the toxin coregulated pilus appear to be induced early in infection and repressed late in infection before exiting the human gastrointestinal tract. Other genes that are induced late during infection are believed to be important for the establishment of the hyperinfective phenotype exhibited by human shed vibrios, and for survival in the aquatic ecosystem. The mechanisms that control gene expression in vivo are largely unknown. Quorum sensing has been proposed as one potential mechanism to govern late gene expression in vivo. However, the observation that many epidemic V. cholerae strains are quorum sensing insensitive suggests that other regulatory mechanisms must exist. Our laboratory has shown that diketopiperazines inhibit virulence factor production in V. cholerae. In this grant we will test the hypothesis that cyclo(Phe-Pro), a natural diketopiperazine produced by V. cholerae, functions as a signal to modulate virulence gene expression independent of the known quorum sensing systems.
Two specific aims are proposed.
In specific aim 1 we will characterize cyclo(Phe-Pro) and define genes that are involved in its synthesis .
In specific aim 2 we will define the mechanism by which cyclo(Phe-Pro) regulates virulence factor production. These studies will shed light on a novel regulatory system that controls virulence factor production and may facilitate the future development of novel therapeutic approaches for treatment of cholera.

Public Health Relevance

The proposed research will characterize a potential chemical signal that is involved in the regulated expression of virulence factor production in Vibrio cholerae. Characterization of this chemical signal will advance our understanding of how Vibrio cholerae causes disease and may elucidate potential therapeutic approaches to control the spread of cholera.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Bina, X Renee; Howard, Mondraya F; Taylor-Mulneix, Dawn L et al. (2018) The Vibrio cholerae RND efflux systems impact virulence factor production and adaptive responses via periplasmic sensor proteins. PLoS Pathog 14:e1006804
Kunkle, Dillon E; Bina, X Renee; Bina, James E (2017) The Vibrio cholerae VexGH RND Efflux System Maintains Cellular Homeostasis by Effluxing Vibriobactin. MBio 8:
Bina, X Renee; Howard, Mondraya F; Ante, Vanessa M et al. (2016) Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes. Infect Immun 84:3161-3171
Ante, Vanessa M; Bina, X Renee; Bina, James E (2015) The LysR-type regulator LeuO regulates the acid tolerance response in Vibrio cholerae. Microbiology 161:2434-43
Taylor, Dawn L; Ante, Vanessa M; Bina, X Renee et al. (2015) Substrate-dependent activation of the Vibrio cholerae vexAB RND efflux system requires vexR. PLoS One 10:e0117890
Ante, Vanessa M; Bina, X Renee; Howard, Mondraya F et al. (2015) Vibrio cholerae leuO Transcription Is Positively Regulated by ToxR and Contributes to Bile Resistance. J Bacteriol 197:3499-510
Vikram, Amit; Ante, Vanessa M; Bina, X Renee et al. (2014) Cyclo(valine-valine) inhibits Vibrio cholerae virulence gene expression. Microbiology 160:1054-62
Bina, X Renee; Wong, Eileen A; Bina, Thomas F et al. (2014) Construction of a tetracycline inducible expression vector and characterization of its use in Vibrio cholerae. Plasmid 76:87-94
Taylor, Dawn L; Bina, X Renee; Slamti, Leyla et al. (2014) Reciprocal regulation of resistance-nodulation-division efflux systems and the Cpx two-component system in Vibrio cholerae. Infect Immun 82:2980-91
Bina, X Renee; Taylor, Dawn L; Vikram, Amit et al. (2013) Vibrio cholerae ToxR downregulates virulence factor production in response to cyclo(Phe-Pro). MBio 4:e00366-13

Showing the most recent 10 out of 11 publications