Vibrio cholerae is the causative agent of cholera, an acute life-threatening diarrhea disease. Cholera epidemics occur with seasonal regularity in endemic areas, such as the Ganges Delta region of South Asia. Cholera epidemics in 2010 in Africa, Pakistan, and Haiti remind us that further investigation of this disease is warranted. The ability of V. cholerae strains to cause severe enteric infection in humans depends on their virulence gene content. Bacterial viruses infecting Vibrio species (vibriophages/phages) are known to play a critical role in the transmission of the virulence genes among different strains of V. cholerae (e.g., cholera toxin genes via the filamentous phage CTXf). Furthermore, our fieldwork in Bangladesh has provided direct evidence that lytic vibriophages seemly end cholera epidemics through predation and influencing infectivity. The objective of this proposal is to learn how vibriophages drive the emergence of new pathogenic clones of V. cholerae through horizontal gene transfer, predation, and other biological interactions that affect properties such as biofilm formation, infectivity and environmental persistence. We will approach this problem with six specific aims 1) we will attempt to reconstruct the chromosomal arrangement of filamentous prophages found in the 7th pandemic strain, the most successful clone of toxigenic V. cholerae; 2) we will study the formation of hybrid filamentous phages encoding virulence properties and different host range; 3) we will use comparative genome sequence analysis of both phages and V. cholerae isolates to deduce the mechanisms of phage- resistance and displacement phages in Bangladesh aquatic environment; 4) we will utilize biofilm-degrading phages to study the effect of biofilm dissociation on V. cholerae infectivity and persistence in th environment; 5) we will test the ability of phages to mediate transfer of virulence genes or to produce virulence factors such as inflammatory molecules, cytotoxins and enterotoxins; 6) we will construct genetically marked phages suitable for environmental release and accurate subsequent molecular tracking in water and patients.

Public Health Relevance

The proposed project will test the hypothesis that viruses active on the bacterium Vibrio cholerae, play many undefined roles in the ecology of this pathogen including specialized forms of horizontal gene transfer, selection of emergent clones, production of virulence factors, and modulation of infectivity. Information gained from these studies may lead to new effective ways to control cholera.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068851-12
Application #
8919900
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Janes, Daniel E
Project Start
2003-09-01
Project End
2017-01-31
Budget Start
2015-08-01
Budget End
2017-01-31
Support Year
12
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Hoque, M Mozammel; Naser, Iftekhar Bin; Bari, S M Nayeemul et al. (2016) Quorum Regulated Resistance of Vibrio cholerae against Environmental Bacteriophages. Sci Rep 6:37956
Kamruzzaman, M; Robins, William Paul; Bari, S M Nayeemul et al. (2014) RS1 satellite phage promotes diversity of toxigenic Vibrio cholerae by driving CTX prophage loss and elimination of lysogenic immunity. Infect Immun 82:3636-43
Faruque, Shah M (2014) Role of phages in the epidemiology of cholera. Curr Top Microbiol Immunol 379:165-80
Suzuki, Masato; Danilchanka, Olga; Mekalanos, John J (2014) Vibrio cholerae T3SS effector VopE modulates mitochondrial dynamics and innate immune signaling by targeting Miro GTPases. Cell Host Microbe 16:581-91
Robins, William P; Mekalanos, John J (2014) Genomic science in understanding cholera outbreaks and evolution of Vibrio cholerae as a human pathogen. Curr Top Microbiol Immunol 379:211-29
Yingkajorn, Mingkwan; Sermwitayawong, Natthawan; Palittapongarnpimp, Prasit et al. (2014) Vibrio parahaemolyticus and its specific bacteriophages as an indicator in cockles (Anadara granosa) for the risk of V. parahaemolyticus infection in Southern Thailand. Microb Ecol 67:849-56
Bari, S M Nayeemul; Roky, M Kamruzzaman; Mohiuddin, M et al. (2013) Quorum-sensing autoinducers resuscitate dormant Vibrio cholerae in environmental water samples. Proc Natl Acad Sci U S A 110:9926-31
Robins, William P; Faruque, Shah M; Mekalanos, John J (2013) Coupling mutagenesis and parallel deep sequencing to probe essential residues in a genome or gene. Proc Natl Acad Sci U S A 110:E848-57
Seed, Kimberley D; Faruque, Shah M; Mekalanos, John J et al. (2012) Phase variable O antigen biosynthetic genes control expression of the major protective antigen and bacteriophage receptor in Vibrio cholerae O1. PLoS Pathog 8:e1002917
Bashir, Ali; Klammer, Aaron; Robins, William P et al. (2012) A hybrid approach for the automated finishing of bacterial genomes. Nat Biotechnol 30:701-707

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