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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI102584-01A1
Application #
8598434
Study Section
Special Emphasis Panel (ZRG1-IDM-S (03))
Program Officer
Hall, Robert H
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$428,277
Indirect Cost
$117,646
Name
University of California Santa Cruz
Department
Public Health & Prev Medicine
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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Roelofs, Kevin G; Jones, Christopher J; Helman, Sarah R et al. (2015) Systematic Identification of Cyclic-di-GMP Binding Proteins in Vibrio cholerae Reveals a Novel Class of Cyclic-di-GMP-Binding ATPases Associated with Type II Secretion Systems. PLoS Pathog 11:e1005232

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