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Vibrio cholerae genomic diversity within and between patients

Inès Levade, Yves Terrat, Jean-Baptiste Leducq, Ana A. Weil, Leslie M. Mayo-Smith, Fahima Chowdhury, Ashraful I. Khan, Jacques Boncy, Josiane Buteau, Louise C. Ivers, Edward T. Ryan, Richelle C. Charles, Stephen B. Calderwood, Firdausi Qadri, Jason B. Harris, Regina C. LaRocque, View ORCID ProfileB. Jesse Shapiro
doi: https://doi.org/10.1101/169292
Inès Levade
1Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.
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Yves Terrat
1Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.
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Jean-Baptiste Leducq
1Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.
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Ana A. Weil
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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Leslie M. Mayo-Smith
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
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Fahima Chowdhury
4Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
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Ashraful I. Khan
4Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
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Jacques Boncy
5National Public Health Laboratory, Ministry of Public Health and Population, Port-au-Prince, Haiti.
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Josiane Buteau
5National Public Health Laboratory, Ministry of Public Health and Population, Port-au-Prince, Haiti.
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Louise C. Ivers
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
6Division of Global Health Equity, Brigham and Women’s Hospital, Boston, Massachusetts USA
7Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA
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Edward T. Ryan
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
8Department of Immunology & Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA
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Richelle C. Charles
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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Stephen B. Calderwood
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
9Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA
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Firdausi Qadri
4Center for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
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Jason B. Harris
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
10Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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Regina C. LaRocque
2Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
3Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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B. Jesse Shapiro
1Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.
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  • ORCID record for B. Jesse Shapiro
  • For correspondence: jesse.shapiro@umontreal.ca
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Abstract

Cholera is a severe, waterborne diarrheal 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 nonsynonymous 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.

Author Summary Vibrio cholerae is the etiological agent of cholera, a severe diarrheal disease endemic to Bangladesh and responsible for global outbreaks, including one ongoing in Haiti. Certain bacterial pathogens can evolve and diversify within the human host, often altering virulence and antibiotic resistance. However, most examples of within-host evolution have come from chronic infections, in which the pathogen has sufficient time to mutate and diversify, and little attention has been paid to more acute infections such as the one caused by V. cholerae. The goal of this study was to measure the extent of within-host evolution of V. cholerae within individual infected patients. By sequencing multiple bacterial isolates_from each of eight patients from Bangladesh and Haiti, we found that cholera patients can harbor a diverse population of V. cholerae. As expected for an acute infection, this diversity is limited, ranging from zero to three point mutations (single nucleotide variants) per patient. However, gene gain/loss events are more prevalent than point mutations, occurring in every single patient, and sometimes involving the transfer of dozens of genes on plasmids. Even if rare, point mutations and gene gain/loss events may be maintained by natural selection, and can alter clinically-and environmentally-relevant phenotypes such as biofilm formation. Therefore, within-patient evolution has the potential to impact clinical and epidemiological outcomes. Together, our results demonstrate that within-patient evolution may be a general feature of both acute and chronic infections, and that gene gain/loss may be an important but under-appreciated feature of within-host evolution.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 28, 2017.
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Vibrio cholerae genomic diversity within and between patients
Inès Levade, Yves Terrat, Jean-Baptiste Leducq, Ana A. Weil, Leslie M. Mayo-Smith, Fahima Chowdhury, Ashraful I. Khan, Jacques Boncy, Josiane Buteau, Louise C. Ivers, Edward T. Ryan, Richelle C. Charles, Stephen B. Calderwood, Firdausi Qadri, Jason B. Harris, Regina C. LaRocque, B. Jesse Shapiro
bioRxiv 169292; doi: https://doi.org/10.1101/169292
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Vibrio cholerae genomic diversity within and between patients
Inès Levade, Yves Terrat, Jean-Baptiste Leducq, Ana A. Weil, Leslie M. Mayo-Smith, Fahima Chowdhury, Ashraful I. Khan, Jacques Boncy, Josiane Buteau, Louise C. Ivers, Edward T. Ryan, Richelle C. Charles, Stephen B. Calderwood, Firdausi Qadri, Jason B. Harris, Regina C. LaRocque, B. Jesse Shapiro
bioRxiv 169292; doi: https://doi.org/10.1101/169292

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