Abstract
Pandemic V. cholerae strains in the O1 serogroup have 2 biotypes: classical and El Tor. The classical biotype strains of the sixth pandemic, which encode the classical type cholera toxin (CT), have been replaced by El Tor biotype strains of the seventh pandemic. The prototype El Tor strains that produce biotype-specific cholera toxin are being replaced by atypical El Tor variants that harbor classical cholera toxin. Atypical El Tor strains are categorized into 2 groups, Wave 2 and Wave 3 strains, based on genomic variations and the CTX phage that they harbor. Whole-genome analysis of V. cholerae strains in the seventh cholera pandemic has demonstrated gradual changes in the genome of prototype and atypical El Tor strains, indicating that atypical strains arose from the prototype strains by replacing the CTX phages. We examined the molecular mechanisms that effected the emergence of El Tor strains with classical cholera toxin-carrying phage. We isolated an intermediary V. cholerae strain that carried two different CTX phages that encode El Tor and classical cholera toxin, respectively. We show here that the intermediary strain can be converted into various Wave 2 strains and can act as the source of the novel mosaic CTX phages. These results imply that the Wave 2 and Wave 3 strains may have been generated from such intermediary strains in nature. Prototype El Tor strains can become Wave 3 strains by excision of CTX-1 and re-equipping with the new CTX phages. Our data suggest that inter-chromosomal recombination between 2 types of CTX phages is possible when a host bacterial cell is infected by multiple CTX phages. Our study also provides molecular insights into population changes in V. cholerae in the absence of significant changes to the genome but by replacement of the CTX prophage that they harbor.
Highlights
Vibrio cholerae O1 serogroup strains have been categorized into 2 biotypes - classical and El Tor -based on microbiological properties and the CTX prophage that they harbor [1,2]
The CTX-3 prophages in V. cholerae isolates belonging to Wave 3 strains that were collected in Vietnam and India contained 3 SNPs in rstA compared with CTX-1 of N16961 and V212-1, as shown in Table 1 [8,18]
It is assumed that prototype El Tor strains have been extinguished, because only atypical El Tor strains have since been isolated from cholera patients globally [6]
Summary
Vibrio cholerae O1 serogroup strains have been categorized into 2 biotypes - classical and El Tor -based on microbiological properties and the CTX prophage that they harbor [1,2]. Classical biotype strains contain the classical CTX prophage (CTXcla), and El Tor strains are believed to contain the El Tor CTX prophage (CTXEl Tor, or CTX-1). The CTX phage comprises 10 genes (rstR, rstA, rstB, psh, cep, orfU, ace, zot, ctxA, and ctxB). Whereas rstR is phage type-specific, other genes differ between phages by several SNPs, except for ctxA, which is identical in the 2 phages [3]. The binding subunit of cholera toxin (CTB) is encoded by ctxB, and the CTBs between phages differ by 2 of their 125 amino acids (residues 39 and 68) [1]. An evolutionary model of pathogenic V. cholerae O1 strains, in which El Tor biotype strains acquired only the El Tor CTX phage, whereas the classical strains obtained the classical phage, has been widely accepted [4]
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