Vibrio cholerae is a facultative pathogen and the causative agent of cholera. Hallmarks of the disease include profuse watery diarrhea resulting from the action of secreted cholera toxin, and deadly, explosive outbreaks. The strong link between epidemics and human overcrowding in areas with untreated drinking water suggests an efficient mode of fecal-oral transmission via an aquatic intermediate. In support of this notion, we discovered that V. cholerae exit cholera victims in a heightened state of transmissibility (referred to as """"""""hyperinfectivity""""""""), which persists for several hours after shedding into pond water. Knowledge of the molecular basis for this phenotype, and a general characterization of this transmissible form of V. cholerae, would contribute to the design of vaccines to prevent cholera at the initial stage of infection. In prior work, we discovered that motility in the absence of chemotaxis is one determinant of hyperinfectivity. To identify additional determinants aiding in transmission, we measured global transcriptional changes in human-shed V. cholerae during the transition to an aquatic microcosm. This analysis revealed a number of regulators and effectors that potentially contribute to cholera transmission. In related work, we used a genetic selection to identify genes that are `pre-induced'at late stages of infection and which subsequently play roles in the transition of V. cholerae to aquatic environments.
In Aims 1 and 2 of this project, we propose to determine if genes regulated late in infection or in cholera stool play important roles in the transition to pond water and in hyperinfectivity. Transcriptional regulators with important roles in these phenotypes will be further analyzed by transcriptional profiling to define their corresponding regulons.
In Aim 2, we also propose to measure and correlate changes in the transcriptome and proteome of cholera stool V. cholerae during the transition to pond water.
In Aim 3, we propose to apply knowledge of the effectors of transmission to develop and test a mucosal vaccine in a mouse maternal model of immunization and challenge of pups. We hypothesize that an acellular vaccine expressing a repertoire of antigens that are stably expressed on the surface of transmissible forms of V. cholerae will provide enhanced protection to challenge by the transmissible form of this pathogen. These studies will establish a basis for understanding both the hyperinfective phenotype of V. cholerae and its transition to aquatic environments. This knowledge will enhance our understanding of transmission of this and perhaps other water-borne pathogens, helping pave the way to development of novel vaccines that target transmissible forms of facultative pathogens.

Public Health Relevance

Many of the diseases that afflict humans are caused by microbes transmitted via contaminated water supplies. The biology of pathogens in aquatic reservoirs and the traits they have evolved to aid in their transmission are largely unknown. Our project will use the causative agent of cholera as a model pathogen to uncover such evolved traits, and will use the knowledge gained to test a novel vaccine that targets the transmissible form of the pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055058-09
Application #
8211006
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
2003-05-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$404,291
Indirect Cost
$159,266
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Molina-Quiroz, Roberto C; Silva-Valenzuela, Cecilia; Brewster, Jennifer et al. (2018) Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic Escherichia coli. MBio 9:
Manneh-Roussel, Jainaba; Haycocks, James R J; Magán, Andrés et al. (2018) cAMP Receptor Protein Controls Vibrio cholerae Gene Expression in Response to Host Colonization. MBio 9:
Reyes-Robles, Tamara; Dillard, Rebecca S; Cairns, Lynne S et al. (2018) Vibrio cholerae outer membrane vesicles inhibit bacteriophage infection. J Bacteriol :
Shull, Lauren M; Camilli, Andrew (2018) Transposon Sequencing of Vibrio cholerae in the Infant Rabbit Model of Cholera. Methods Mol Biol 1839:103-116
Li, Peng; Kinch, Lisa N; Ray, Ann et al. (2017) Acute Hepatopancreatic Necrosis Disease-Causing Vibrio parahaemolyticus Strains Maintain an Antibacterial Type VI Secretion System with Versatile Effector Repertoires. Appl Environ Microbiol 83:
Yen, Minmin; Cairns, Lynne S; Camilli, Andrew (2017) A cocktail of three virulent bacteriophages prevents Vibrio cholerae infection in animal models. Nat Commun 8:14187
Wang, Zhu; Lazinski, David W; Camilli, Andrew (2017) Immunity Provided by an Outer Membrane Vesicle Cholera Vaccine Is Due to O-Antigen-Specific Antibodies Inhibiting Bacterial Motility. Infect Immun 85:
Silva-Valenzuela, Cecilia A; Lazinski, David W; Kahne, Shoshanna C et al. (2017) Growth arrest and a persister state enable resistance to osmotic shock and facilitate dissemination of Vibrio cholerae. ISME J 11:2718-2728
McDonough, EmilyKate; Kamp, Heather; Camilli, Andrew (2016) Vibrio cholerae phosphatases required for the utilization of nucleotides and extracellular DNA as phosphate sources. Mol Microbiol 99:453-69

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