Evidence for several waves of global transmission in the seventh cholera pandemic

Abstract

Vibrio cholerae is a globally important pathogen that is endemic in many areas of the world and causes 3-5 million reported cases of cholera every year. Historically, there have been seven acknowledged cholera pandemics; recent outbreaks in Zimbabwe and Haiti are included in the seventh and ongoing pandemic. Only isolates in serogroup O1 (consisting of two biotypes known as 'classical' and 'El Tor') and the derivative O139 can cause epidemic cholera. It is believed that the first six cholera pandemics were caused by the classical biotype, but El Tor has subsequently spread globally and replaced the classical biotype in the current pandemic. Detailed molecular epidemiological mapping of cholera has been compromised by a reliance on sub-genomic regions such as mobile elements to infer relationships, making El Tor isolates associated with the seventh pandemic seem superficially diverse. To understand the underlying phylogeny of the lineage responsible for the current pandemic, we identified high-resolution markers (single nucleotide polymorphisms; SNPs) in 154 whole-genome sequences of globally and temporally representative V. cholerae isolates. Using this phylogeny, we show here that the seventh pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950s, and identify several transcontinental transmission events. Additionally, we show how the acquisition of the SXT family of antibiotic resistance elements has shaped pandemic spread, and show that this family was first acquired at least ten years before its discovery in V. cholerae.

Fig 1

A maximum likelihood phylogenetic tree of the 7^th pandemic lineage of V. cholerae based on the SNP differences across the whole core genome, excluding likely recombination events. The pre-7^th pandemic isolate M66 was used as an outgroup to root the tree. Branches are colored based on the region of isolation of the strains. The branches representing the three major waves are indicated on the far right, and the nodes representing the most recent common ancestors (MRCA) of the 7^th pandemic, and subsequent waves 2 and 3, are indicated with arrows, and labeled with inferred dates. The presence and type of CTX and SXT elements in each strain are shown to the right of the tree. The presence of TLC and RS1 elements are shown but their number and position, respectively, are arbitrarily assigned. A-D mark cases of sporadic intercontinental transmission. The dates shown are the median estimates for the indicated nodes, taken from the results of the BEAST analysis. * indicates where no data was available and the scale is given as the number of substitutions per variable site.

Fig 2

Transmission events inferred for the 7^th Pandemic phylogenetic tree drawn on a global map. The date ranges shown for transmission events are taken from the BEAST analysis, and represent the median values for the MRCA of the transmitted strains (later bound), and the MRCA of the transmitted strains and their closest relative from the source location (earlier bound).