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 #
2R01GM068851-09A1
Application #
8369505
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Eckstrand, Irene A
Project Start
2003-09-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$365,978
Indirect Cost
$109,779
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
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
Zahid, M Shamim Hasan; Waise, Zaved; Kamruzzaman, M et al. (2011) An experimental study of phage mediated bactericidal selection & emergence of the El Tor Vibrio cholerae. Indian J Med Res 133:218-24
Kamruzzaman, M; Udden, S M Nashir; Cameron, D Ewen et al. (2010) Quorum-regulated biofilms enhance the development of conditionally viable, environmental Vibrio cholerae. Proc Natl Acad Sci U S A 107:1588-93
Zahid, M Shamim Hasan; Waise, T M Zaved; Kamruzzaman, M et al. (2010) The cyclic AMP (cAMP)-cAMP receptor protein signaling system mediates resistance of Vibrio cholerae O1 strains to multiple environmental bacteriophages. Appl Environ Microbiol 76:4233-40
Hassan, Faizule; Kamruzzaman, M; Mekalanos, John J et al. (2010) Satellite phage TLC? enables toxigenic conversion by CTX phage through dif site alteration. Nature 467:982-5

Showing the most recent 10 out of 23 publications