Vibrio cholerae causes the disease cholera, an important public health problem worldwide. V. cholerae?s ability to cause epidemics is tied to its dissemination and survival in aquatic habitats and its transmission to the human host. The pathogen?s ability to form biofilms (i.e., matrix-enclosed, surface-associated communities) is crucial for its survival in aquatic habitats between epidemics and is advantageous for host-to-host transmission during epidemics. The signaling nucleotide cyclic dimeric guanosine monophosphate (c-diGMP) is broadly conserved in bacteria and is a key regulator of biofilm formation. Understanding of how c-diGMP controls biofilm formation, which environmental signals modulate c-diGMP levels and biofilm formation, and consequences of c-diGMP signaling in V. cholerae infectivity, transmission and dissemination, is limited. These information gaps will addressed by focusing on two specific aims. 1) Analyze c-diGMP signaling pathways that control biofilm formation dynamics; and 2) Analyze activation of c-diGMP signaling pathways and their consequences in V. cholerae infection cycle. Under the first aim, the molecular mechanism(s) through which c-diGMP controls production of the type IVa MSHA pilus, the primary component of initial surface attachment will be determined using structural and biochemical approaches. The down-stream c-diGMP signaling pathways initiated upon surface attachment will be analyzed by employing microscopy-based community tracking methods to measure motility, division, and second messenger signal levels. The mechanism by which specific key c-diGMP signaling proteins act to control surface attachment and biofilm matrix production will be determined using combination of genetic and biochemical approaches. Under the second aim, the mechanism of activation of key c-diGMP signaling proteins will be determined using structural and ligand binding studies. The role of c-diGMP signaling in in vivo biofilm formation, in V. cholerae transmission and dissemination will also be investigated, using state- of-the-art imaging tools and novel c-diGMP sensors. The proposed work will greatly advance the understanding of how c-diGMP signaling operates, identify the inputs that influence c-diGMP production and degradation, and unveil the biological consequences of c-diGMP signaling. The proposed work promises molecular/mechanistic insights that will allow us to devise ways to control c-di-GMP signal transduction pathways governing motility and biofilm formation, ultimately providing targets for the development of inhibitors of V. cholerae transmission.
Infectivity and transmission of Vibrio cholerae, the agent of the disease cholera, is significantly enhanced by its? ability to form and survive in encapsulated multi-cellular communities known as biofilms. In V. cholerae, the signaling molecule, c-diGMP, is crucial for modulating bacterial motility and biofilm formation through ill-defined signaling pathways. This proposal seeks to further define and determine impacts of these pathways on the V. cholerae infection cycle; as elucidating these signaling pathways and their role in biofilm formation could lend to the development of novel therapeutics for the attenuation of V. cholerae biofilm-associated infections, potentially as well as biofilm-associated infections from other pathogenic bacteria.
| Lee, Calvin K; de Anda, Jaime; Baker, Amy E et al. (2018) Multigenerational memory and adaptive adhesion in early bacterial biofilm communities. Proc Natl Acad Sci U S A 115:4471-4476 |
| Cheng, Andrew T; Zamorano-Sánchez, David; Teschler, Jennifer K et al. (2018) NtrC Adds a New Node to the Complex Regulatory Network of Biofilm Formation and vps Expression in Vibrio cholerae. J Bacteriol 200: |
| Conner, Jenna G; Zamorano-Sánchez, David; Park, Jin Hwan et al. (2017) The ins and outs of cyclic di-GMP signaling in Vibrio cholerae. Curr Opin Microbiol 36:20-29 |
| de Anda, Jaime; Lee, Ernest Y; Lee, Calvin K et al. (2017) High-Speed ""4D"" Computational Microscopy of Bacterial Surface Motility. ACS Nano 11:9340-9351 |
| Joshi, Avatar; Kostiuk, Benjamin; Rogers, Andrew et al. (2017) Rules of Engagement: The Type VI Secretion System in Vibrio cholerae. Trends Microbiol 25:267-279 |
| Townsley, Loni; Sison Mangus, Marilou P; Mehic, Sanjin et al. (2016) Response of Vibrio cholerae to Low-Temperature Shifts: CspV Regulation of Type VI Secretion, Biofilm Formation, and Association with Zooplankton. Appl Environ Microbiol 82:4441-52 |
| Bennett, Rachel R; Lee, Calvin K; De Anda, Jaime et al. (2016) Species-dependent hydrodynamics of flagellum-tethered bacteria in early biofilm development. J R Soc Interface 13:20150966 |
| O'Toole, George A; Wong, Gerard Cl (2016) Sensational biofilms: surface sensing in bacteria. Curr Opin Microbiol 30:139-146 |
| Wang, Yu-Chuan; Chin, Ko-Hsin; Tu, Zhi-Le et al. (2016) Nucleotide binding by the widespread high-affinity cyclic di-GMP receptor MshEN domain. Nat Commun 7:12481 |
| Satchell, Karla J F; Jones, Christopher J; Wong, Jennifer et al. (2016) Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain. Infect Immun 84:2473-81 |
Showing the most recent 10 out of 18 publications
