Vibrio cholerae, the causative agent of the worldwide health pandemic cholera, uses both quorum sensing (QS) and cyclic di-GMP (c-diGMP) to regulate biofilm formation and virulence. QS is a process by which bacteria secrete small, chemical signals to count their numbers in a population and control group behavior accordingly. c-diGMP is a recently discovered second messenger intracellular signaling molecule ubiquitous in bacteria. I have recently discovered a novel connection between QS and c-diGMP in V. cholerae. To answer some of the fundamental question about c-diGMP, and further understand its connection to QS, this research proposes to:
Aim 1. Identify the transcriptional components that couple c-diGMP to alterations in gene expression using genetic screens;
Aim 2. Identify specific ligands of GGDEF/EAL proteins in V. cholerae using bioinformatics and a high-throughput chemical screen;
and Aim 3. Utilize X-ray crystallography to determine how signal recognition by GGDEF and EAL proteins modulates enzymatic activity. As both QS and c-diGMP control virulence in V. cholerae and numerous other bacteria pathogens, it is my hope that this work could lead to novel therapeutic approaches for the treatment of bacterial disease. 'Bacteria sense multiple small chemical signals to adapt and respond to their environment. These chemical signals are often control the ability of bacteria to cause disease. My research in Vibrio cholerae seeks to unravel the nature of these signals, and how bacteria respond to them, to develop novel therapeutic approaches to treat bacterial infections.

Public Health Relevance

The K22 Research Scholar Development Award will allow me to support members of my laboratory (graduate students, technician, and/or post-docs) during the first two years of my new faculty position. This will allow me to develop research projects that will form the basis of one or more R01 grants.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K22)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Hall, Robert H
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Michigan State University
Schools of Osteopathic Medicine
East Lansing
United States
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Sloup, Rudolph E; Konal, Ashley E; Severin, Geoffrey B et al. (2017) Cyclic Di-GMP and VpsR Induce the Expression of Type II Secretion in Vibrio cholerae. J Bacteriol 199:
Srivastava, Disha; Waters, Christopher M (2015) A Filter Binding Assay to Quantify the Association of Cyclic di-GMP to Proteins. Bio Protoc 5:
Koestler, Benjamin J; Waters, Christopher M (2014) Bile acids and bicarbonate inversely regulate intracellular cyclic di-GMP in Vibrio cholerae. Infect Immun 82:3002-14
Hunter, Jessica L; Severin, Geoffrey B; Koestler, Benjamin J et al. (2014) The Vibrio cholerae diguanylate cyclase VCA0965 has an AGDEF active site and synthesizes cyclic di-GMP. BMC Microbiol 14:22
Edmunds, Adam C; Castiblanco, Luisa F; Sundin, George W et al. (2013) Cyclic Di-GMP modulates the disease progression of Erwinia amylovora. J Bacteriol 195:2155-65
Srivastava, Disha; Hsieh, Meng-Lun; Khataokar, Atul et al. (2013) Cyclic di-GMP inhibits Vibrio cholerae motility by repressing induction of transcription and inducing extracellular polysaccharide production. Mol Microbiol 90:1262-76
Bellows, Lauren E; Koestler, Benjamin J; Karaba, Sara M et al. (2012) Hfq-dependent, co-ordinate control of cyclic diguanylate synthesis and catabolism in the plague pathogen Yersinia pestis. Mol Microbiol 86:661-74
Srivastava, Disha; Waters, Christopher M (2012) A tangled web: regulatory connections between quorum sensing and cyclic Di-GMP. J Bacteriol 194:4485-93
Sambanthamoorthy, Karthik; Sloup, Rudolph E; Parashar, Vijay et al. (2012) Identification of small molecules that antagonize diguanylate cyclase enzymes to inhibit biofilm formation. Antimicrob Agents Chemother 56:5202-11
Beckmann, Benjamin E; Knoester, David B; Connelly, Brian D et al. (2012) Evolution of resistance to quorum quenching in digital organisms. Artif Life 18:291-310

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