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Microb Genom. 2017 Dec;3(12). doi: 10.1099/mgen.0.000142.

Vibrio cholerae genomic diversity within and between patients.

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1​Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.
2​Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
3​Department of Medicine, Harvard Medical School, Boston, MA, USA.
4​Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
5​National Public Health Laboratory, Ministry of Public Health and Population, Port-au-Prince, Haiti.
6​Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA.
7​Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
8​Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.
9​Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
10​Department of Pediatrics, Harvard Medical School, Boston, MA, USA.


Cholera is a severe, water-borne diarrhoeal disease caused by toxin-producing strains of the bacterium Vibrio cholerae. Comparative genomics has revealed 'waves' of cholera transmission and evolution, in which clones are successively replaced over decades and centuries. However, the extent of V. cholerae genetic diversity within an epidemic or even within an individual patient is poorly understood. Here, we characterized V. cholerae genomic diversity at a micro-epidemiological level within and between individual patients from Bangladesh and Haiti. To capture within-patient diversity, we isolated multiple (8 to 20) V. cholerae colonies from each of eight patients, sequenced their genomes and identified point mutations and gene gain/loss events. We found limited but detectable diversity at the level of point mutations within hosts (zero to three single nucleotide variants within each patient), and comparatively higher gene content variation within hosts (at least one gain/loss event per patient, and up to 103 events in one patient). Much of the gene content variation appeared to be due to gain and loss of phage and plasmids within the V. cholerae population, with occasional exchanges between V. cholerae and other members of the gut microbiota. We also show that certain intra-host variants have phenotypic consequences. For example, the acquisition of a Bacteroides plasmid and non-synonymous mutations in a sensor histidine kinase gene both reduced biofilm formation, an important trait for environmental survival. Together, our results show that V. cholerae is measurably evolving within patients, with possible implications for disease outcomes and transmission dynamics.


Vibrio cholerae; biofilm; comparative genomics; horizontal gene transfer; within-host evolution

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