Vibrio cholerae is a water-borne pathogen and causative agent of cholera. Its ability to disseminate and persist in fresh water establishes a reservoir from which outbreaks occur. However, the strong link between epidemics and overcrowding suggests a more efficient mode of fecal-oral transmission, which is supported by studies showing rapid and efficient spread of cholera within households. Knowledge of the bacterial and environmental factors that influence dissemination and transmission would contribute to a better understanding of cholera outbreaks, and to better public health measures to prevent them. We showed that V. cholerae exits humans in a physiological state(s) primed for dissemination and transmission. However, we found that the V. cholerae genes that contribute to dissemination and transmission are largely distinct, and that expression of individual genes occurs in only a fraction of the cells being shed. Thus, we hypothesize that distinct subpopulations are shed, one primed for dissemination and the other for rapid transmission.
In Aim 1, we will demonstrate and characterize these different subpopulations by physically separating them for phenotypic and gene expression studies. In clinical samples, we identified a lytic phage that closely associates with epidemic V. cholerae. We discovered a dynamic arms race between this phage and V. cholerae that is occurring within humans and aquatic environment.
In Aim 2, we will determine how dynamics of phage predation impact dissemination and transmission of V. cholerae. We found that vaccination with purified V. cholerae outer membrane vesicles elicits antibodies recognizing LPS O-antigen, that these antibodies are sufficient for protection, and that V. cholerae passing through an immune host are rendered avirulent.
In Aim 3, we will examine the mechanism of protection and blocking of transmission. These studies will establish a basis for understanding how V. cholerae simultaneously promotes dissemination and transmission, how pervasive lytic phages impact these processes, and how vaccination blocks infection and transmission. This knowledge will enhance understanding of water- borne pathogens and help pave the way to development of interventions that target the transmissible and disseminative forms of such pathogens.

Public Health Relevance

Water-borne pathogens contribute significantly to human disease, and yet, knowledge on how such pathogens optimize their transmission and dissemination, and how lytic phages (viruses that kill bacteria) influence these processes, are largely unknown. Our project will use the causative agent of cholera and its associated lytic phages as models to characterize these processes. In addition, our project will examine the mechanism of protection afforded by a mucosally delivered cholera vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI055058-11A1
Application #
8886025
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hall, Robert H
Project Start
2003-05-15
Project End
2020-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
11
Fiscal Year
2015
Total Cost
$412,500
Indirect Cost
$162,500
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Duncan, Miles C; Forbes, John C; Nguyen, Y et al. (2018) Vibrio cholerae motility exerts drag force to impede attack by the bacterial predator Bdellovibrio bacteriovorus. Nat Commun 9:4757
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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