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Current Pandemic Cholera Strain Developed in Six Stages, Study Finds

NEW YORK (GenomeWeb) – A new study suggests that the so-called El Tor Vibrio cholerae strain behind the most recent cholera pandemic — which started in Indonesia in the early 1960s and is still implicated in millions of cholera cases annually — stemmed from a non-pathogenic form of V. cholerae that was present in the Middle East in the late 1800s.

In a study appearing online this week in the Proceedings of the National Academy of Sciences, researchers from China and Australia described findings from a comparative genomics study involving more than a dozen previously sequenced or newly sequenced El Tor isolates collected over several decades. Based on genetic patterns present before and after the El Tor biotype was implicated in cholera pandemics, they identified six stages in pandemic V. cholerae strain development.

Since its presumed beginnings in South Asia and movement to the Middle East, the El Tor biotype appears to have diversified dramatically, the team found, recombining and taking on new sequences and mutations as it moved from one locale to the next.

"By combining all available historical records and genomic analysis of available pre-seventh pandemic and some early pandemic strains, we revealed the complex six-step evolution of the pandemic strain from its probable origin in South Asia to its non-pathogenic form in the Middle East in [around 1900] to Indonesia in [around 1925], where it evolved into a pandemic strain before becoming widespread in 1961," the authors wrote.

Seven cholera pandemics have been documented over the past two centuries, the team explained, though V. cholerae isolates are only available for the most recent two pandemic events. And those samples suggest that the most recent cholera pandemic did not stem directly from strains involved in the sixth pandemic.

"Long before the seventh pandemic started in 1961, El Tor biotype strains from two small areas had been reported, commonly referred to as Middle East and Makassar strains and collectively as pre-seventh pandemic (or pre-pandemic) strains," the investigators wrote.

To assess the genetics of these pre-pandemic strains and their relationships with dangerous El Tor isolates circulating since the 1960s, the researchers used the PacBio RS instrument to sequence 10 El Tor strains. These included two pre-pandemic Vibrio cholerae isolates from the Middle East; one pre-pandemic isolate from Makassar, Indonesia; four isolates collected between 1961 and 1964 during the early stages of the seventh pandemic; and pre-pandemic-related strains collected in the US, Australia, and China in the 1970s.

A phylogenetic analysis of the new and existing V. cholerae isolates pointed to six branch points in the lineage leading to the pandemic El Tor strain, including several stages of development that seem to coincide with the pathogen's presence in specific geographical regions.

After diverging from the lineage leading to sixth pandemic strains somewhere in Asia, for example, the El Tor strain appears to have moved to the Middle East where it diversified and obtained new genes, but apparently remained non-pathogenic. From there, the strain spread to other parts of the world, the researchers reported, perhaps carried home by pilgrims visiting Mecca.

Through sequential recombination events with other strains in the regions — along with changes to virulence genes and an uptick in mutation rate — the strain seems to have notched closer and closer to its current form, which was officially recognized in Makassar, Indonesia, a busy shipping hub at that time.

As such, the authors noted, "classical biotype strains now thought to have been responsible for the first through sixth pandemics, seem to have played an important role in the evolution of the seventh-pandemic strain, despite the divergence of the classical and El Tor biotype strains much further back."