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. We have identified four QS signaling pathways that 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 ethanolamine and cyclic AMP (cAMP), respectively, are responsible for controlling two of these receptors, CqsR and VpsS.
In Aim 1, we will determine how ethanolamine and other related molecules regulate CqsR.
In Aim 2, we will determine how cAMP regulates VpsS.
In Aim 3, we will define the regulatory hierarchy in the V. cholerae QS circuit. Specifically, we will determine the roles of a recently discovered cyclic dinucleotide called cyclic GMP-AMP in QS gene regulation. 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.
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.
| 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 |
| 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: |
| 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 |
