title: Genomic epidemiology of the Haitian cholera outbreak: a single introduction followed by rapid, extensive, and continued spread characterized the onset of the epidemic.
abstract: For centuries, cholera has been one of the most feared diseases. The causative agent Vibrio cholerae is a waterborne Gram-negative enteric pathogen eliciting a severe watery diarrheal disease. In October 2010, the seventh pandemic reached Haiti, a country that had not experienced cholera for more than a century. By using whole-genome sequence typing and mapping strategies of 116 serotype O1 strains from global sources, including 44 Haitian genomes, we present a detailed reconstructed evolutionary history of the seventh pandemic with a focus on the Haitian outbreak. We catalogued subtle genomic alterations at the nucleotide level in the genome core and architectural rearrangements from whole-genome map comparisons. Isolates closely related to the Haitian isolates caused several recent outbreaks in southern Asia. This study provides evidence for a single-source introduction of cholera from Nepal into Haiti followed by rapid, extensive, and continued clonal expansion. The phylogeographic patterns in both southern Asia and Haiti argue for the rapid dissemination of V. cholerae across the landscape necessitating real-time surveillance efforts to complement the whole-genome epidemiological analysis. As eradication efforts move forward, phylogeographic knowledge will be important for identifying persistent sources and monitoring success at regional levels. The results of molecular and epidemiological analyses of this outbreak suggest that an indigenous Haitian source of V. cholerae is unlikely and that an indigenous source has not contributed to the genomic evolution of this clade.
  
  
  OBJECTIVE
  In this genomic epidemiology study, we have applied high-resolution whole-genome-based sequence typing methodologies on a comprehensive set of genome sequences that have become available in the aftermath of the Haitian cholera epidemic. These sequence resources enabled us to reassess the degree of genomic heterogeneity within the Vibrio cholerae O1 serotype and to refine boundaries and evolutionary relationships. The established phylogenomic framework showed how outbreak isolates fit into the global phylogeographic patterns compared to a comprehensive globally and temporally diverse strain collection and provides strong molecular evidence that points to a nonindigenous source of the 2010 Haitian cholera outbreak and refines epidemiological standards used in outbreak investigations for outbreak inclusion/exclusion following the concept of genomic epidemiology. The generated phylogenomic data have major public health relevance in translating sequence-based information to assist in future diagnostic, epidemiological, surveillance, and forensic studies of cholera.
authors.affiliation: mark.eppinger@utsa.edu paul.keim@nau.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Eppinger
authors.affiliation: Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, Arizona, USA.
authors.forename: Talima
authors.initials: T
authors.lastname: Pearson
authors.affiliation: Department of Biology, University of Texas, San Antonio, Texas, USA.
authors.forename: Sara S K
authors.initials: SS
authors.lastname: Koenig
authors.affiliation: U.S. Geological Survey, Denver Federal Center, Denver, Colorado, USA.
authors.forename: Ofori
authors.initials: O
authors.lastname: Pearson
authors.forename: Nathan
authors.initials: N
authors.lastname: Hicks
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Agrawal
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Sanjar
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Galens
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Daugherty
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Crabtree
authors.affiliation: National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: Rene S
authors.initials: RS
authors.lastname: Hendriksen
authors.affiliation: Division of Pathogen Genomics, Translational Genomics Research Institute (TGen), Flagstaff, Arizona, USA.
authors.forename: Lance B
authors.initials: LB
authors.lastname: Price
authors.affiliation: National Public Health Laboratory, Kathmandu, Nepal.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Upadhyay
authors.affiliation: National Public Health Laboratory, Kathmandu, Nepal.
authors.forename: Geeta
authors.initials: G
authors.lastname: Shakya
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Fraser
authors.affiliation: University of Maryland School of Medicine, Institute for Genome Sciences (IGS), Baltimore, Maryland, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Ravel
authors.affiliation: mark.eppinger@utsa.edu paul.keim@nau.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Keim
mesh_terms: D002771:Cholera / Q000453:epidemiology* / Q000382:microbiology* / Q000635:transmission; D058872:Epidemics; D016680:Genome, Bacterial; D005838:Genotype; D006205:Haiti / Q000453:epidemiology; D017720:Molecular Epidemiology; D058889:Molecular Typing; D009390:Nepal; D058974:Phylogeography; D017422:Sequence Analysis, DNA; D041241:Vibrio cholerae O1 / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification