- Largest study of its kind paves way for improved diagnosis and development of drugs, vaccines

Vibrio cholerae, the bacterial pathogen causing cholera.

An international research team comprising of scientists from Seoul National University (SNU) and the IVI, and research institutions in the U.S. and India elucidated the basis for the emergence of mutated strains of Vibrio cholerae, the causative agent of cholera, and identified an evolutionary mechanism of pathogenic bacteria by analyzing genomic sequences of 23 V. cholerae strains.

Dr. Chun Jongsik, Life Sciences Professor at SNU and Adjunct Scientist at the IVI, and Dr. Kim Dong Wook, Head of Molecular Bacteriology at the IVI, conducted the largest genomic analysis of microorganisms ever publicized in the world. The University of Maryland and the Department of Energy Joint Genome Institute at Los Alamos National Laboratory conducted gene sequencing of V. cholerae, while the SNU and IVI team worked on bioinformatics analysis. The study was published in the online edition of the Proceedings of the National Academy of Sciences on August 31, 2009.

Cholera has been known to plague mankind since antiquity. Historically, there have been seven cholera pandemics. V. cholerae O1 classical biotype was almost exclusively responsible for the sixth pandemic (1899-1923), whereas the seventh pandemic, which has been ongoing since its inception in India in 1962, is caused by the V. cholerae O1 El Tor biotype. Over the past three decades, the O1 classical biotype has not been reported.

However, in 1992, a totally new serogroup of V. cholerae, O139, was identified as the cause of epidemic cholera in the Bay of Bengal, India. There has also been the emergence of a V. cholerae 01 "hybrid," and new pathogenic clones have continued to emerge and re-emerge, hampering global efforts to control cholera.

Dr. Chun Jong-shik and Dr. Kim Dong-wook.

Against this backdrop, the team of international researchers in Korea, U.S. and India conducted genomic sequencing of 23 V. cholerae strains collected at different times since 1910 from various locations in the world, and analyzed them using the latest bioinformatics techniques. The researchers found that transition from the sixth to the seventh pandemic involved an evolutionary change of V. cholerae to a wholly new pathogenic strain in a phenomenon called "shift." They also found that different strains from the present pandemic strain are clones evolved from the same ancestor, and they emerged from a phenomenon called ‘‘drift’’ between the clones.

The researchers discovered that mutated bacteria can emerge every several years, and are spawned primarily by bacteriophages, viruses that infect bacteria. They found that many of the genes that play a key role in triggering disease, including the gene for cholera toxin (the main culprit of diarrhea), move between bacteria due to this virus. Unlike humans, bacteria can transmit and receive genes among each other. The researchers identified about 70 new genetic groups that move between bacteria. They found that as bacteria retain these genetic groups in various combinations, new bacterial strains can emerge.

"The identification of the evolutionary mechanism of pathogenic bacteria has paved the way to promptly cope with newly emerging strains of bacteria, and to efficiently develop vaccines and therapeutics," said Dr. Chun.

A single cholera bacterium has about 4,000 genes (a human has about 25,000 genes). The researchers discovered as many as 6,000 genes from the 23 V. cholerae strains. The researchers believe that the entire pool of genes of V. cholerae existing in nature can amount to hundreds of thousands in number. Accordingly, they predict that a more virulent and infectious mutated bacterial strain can emerge at any time.

The study also provides an important clue to the mechanism of how new strains emerge in other pathogenic bacteria, including Bacillus anthracis (anthrax), Shigella, Salmonella Typhi, Helicobacter pylori, and Streptococcus pneumoniae. Moreover, by using the database developed through the study, scientists can now diagnose a mutated V. cholerae strain that emerges anywhere in the world in a matter of one to two days through genomic analysis. Accurate diagnosis is essential to the development and selection of suitable vaccines and drugs.

IVI Director-General Dr. Clemens said, "By discovering the evolutionary mechanism of the cholera bacterium, the study opens a new chapter in global efforts to prepare for the emergence of new cholera strains, and to develop drugs and vaccines. The study also has provided a new platform to cope with potential crises, through the development of a genomic database for a killer bacterial disease amid growing possibility for cholera outbreaks due to global warming."