Vibrio cholerae, the causative agent of the disease cholera, is an important human pathogen that is an ongoing public health problem in regions of developing countries in the Americas, Asia, and Africa. In many bacteria including V. cholerae, cyclic dimeric guanosine monophosphate (c-diGMP) regulates motility, biofilm formation and virulence. We have a solid general understanding of the basic biochemistry of c-diGMP turnover and c-diGMP-dependent phenotypes, but critical questions remain. These include how does c-diGMP mechanistically control motile to biofilm life style switch in V. cholerae, how do environmental signals control c-di-GMP levels and biofilm formation in V. cholerae, and what are the consequences of c-diGMP signaling in the intestinal and aquatic and phases of V. cholerae life cycle. We will address these questions by focusing on two aims.
In Aim 1, we will determine how specific key c-diGMP signaling proteins and cell surface structures act to control surface-associated motility, elucidate how motility status affects c-diGMP levels, and determine which c-diGMP proteins function together and which cellular proteins they target.
In Aim 2, we will determine molecular mechanisms of environmental regulation of c-diGMP levels and analyze the impact of c-diGMP signaling proteins in V. cholerae aquatic and intestinal life cycles. Our studies will lead to a better understanding of c-diGMP signal transduction pathways that are critical for the life-cycle of V. cholerae and may, therefore, lead to new methods of combating this pathogen, as well as other disease-causing microorganisms that use c-diGMP signaling. This work will also contribute to the basic understanding of the newly emerging, ubiquitous, signal transduction network and, therefore, will be relevant to investigations of similar regulatory systems in a broad range of bacteria.

Public Health Relevance

Nucleotide-based second messengers, such as cyclic dimeric guanosine monophosphate (c- diGMP), play important roles in the physiology of many bacterial pathogens. In particular, c- diGMP affects motility, biofilm formation, and virulence in Vibrio cholerae, the causative agent of the disease cholera. This proposal aims to improve our understanding of c-diGMP signaling, which will allow us to define targets to combat this deadly pathogen in both intestinal and aquatic ecosystems.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-S (03)M)
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Hall, Robert H
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University of California Santa Cruz
Public Health & Prev Medicine
Schools of Arts and Sciences
Santa Cruz
United States
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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
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
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
O'Toole, George A; Wong, Gerard Cl (2016) Sensational biofilms: surface sensing in bacteria. Curr Opin Microbiol 30:139-146
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
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
Conner, Jenna G; Teschler, Jennifer K; Jones, Christopher J et al. (2016) Staying Alive: Vibrio cholerae's Cycle of Environmental Survival, Transmission, and Dissemination. Microbiol Spectr 4:
Rogers, Andrew; Townsley, Loni; Gallego-Hernandez, Ana L et al. (2016) The LonA Protease Regulates Biofilm Formation, Motility, Virulence, and the Type VI Secretion System in Vibrio cholerae. J Bacteriol 198:973-85
Townsley, Loni; Yildiz, Fitnat H (2015) Temperature affects c-di-GMP signalling and biofilm formation in Vibrio cholerae. Environ Microbiol 17:4290-305
Teschler, Jennifer K; Zamorano-Sánchez, David; Utada, Andrew S et al. (2015) Living in the matrix: assembly and control of Vibrio cholerae biofilms. Nat Rev Microbiol 13:255-68

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