The human pathogen Vibrio cholerae, the causative agent of the disease cholera, regulates virulence factor production, biofilm formation, competence, and other important processes through quorum sensing (QS), a cell-cell communication mechanism that relies on the production, detection, and response to chemical signal molecules called autoinducers. QS allows bacteria to coordinate population-wide gene expression and function as coordinated groups. In addition to the two canonical QS signaling pathways, we discovered that two additional chemical sensory receptors integrate into the central QS circuit of V. cholerae. Importantly, we found that disruption of these four sensory pathways altogether renders V. cholerae unable to colonize animal hosts. Our data also suggest that these two newly identified receptors detect certain unidentified extracellular molecules different from the two known autoinducers, CAI-1 and AI-2.
In Aim 1, we will identify and characterize these two new signal molecules. We will also determine the biosynthetic pathways for these signals.
In Aim 2, we will define the signal detection mechanisms for these two new receptors.
In Aim 3, we will determine the contribution from each individual QS receptor in virulence gene expression in vivo. Together, our work will not only define the role of QS in V. cholerae pathogenesis, it will also illustrate how integration of multiple signals results in a coherent response in a bacterial cell-cell communication process. It is now well established that QS is employed by many bacterial species to regulate both harmful and beneficial traits. A long standing goal in the field is to develop pro-QS and/or anti-QS molecules to manipulate bacterial group behaviors. Our hope is to harness the knowledge on QS to enable the design of interference strategies that can be translated into new therapies to combat infectious diseases.

Public Health Relevance

Vibrio cholerae is a globally important pathogen and the burden of cholera is estimated to reach several million cases annually. V. cholerae virulence depends on a cell-cell communication process called quorum sensing that controls the timing of production and release of virulence factors and the formation of biofilms. The investigations proposed here will expand our understanding of how quorum sensing controls virulence in this important pathogen. In addition, this study will facilitate the development of synthetic strategies for controlling V. cholerae virulence and could have significant ramifications for improving human health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Hall, Robert H
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Tufts University
Schools of Medicine
United States
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Severin, Geoffrey B; Ramliden, Miriam S; Hawver, Lisa A et al. (2018) Direct activation of a phospholipase by cyclic GMP-AMP in El Tor Vibrio cholerae. Proc Natl Acad Sci U S A 115:E6048-E6055
Jung, Sarah A; Hawver, Lisa A; Ng, Wai-Leung (2016) Parallel quorum sensing signaling pathways in Vibrio cholerae. Curr Genet 62:255-60
Hawver, Lisa A; Jung, Sarah A; Ng, Wai-Leung (2016) Specificity and complexity in bacterial quorum-sensing systems. FEMS Microbiol Rev 40:738-52
Hawver, Lisa A; Giulietti, Jennifer M; Baleja, James D et al. (2016) Quorum Sensing Coordinates Cooperative Expression of Pyruvate Metabolism Genes To Maintain a Sustainable Environment for Population Stability. MBio 7: