Cholera is a life-threatening infectious disease and a public health hazard. It is caused by a comma-shaped bacterium known as Vibriocholerae .
More than two hundred serogroups of this bacterium are known, of which only O1 and O139 are known to cause such infection that leads to epidemics and pandemics. Most of the serogroups only cause mild cholera-like diarrhea and food-associated outbreaks.
Of these two serogroups, O1 was responsible for seven pandemic waves, only to be temporarily displaced by O139. This emerged late and came up around 1992. It was first spotted in Chennai (then Madras).
It was anticipated that this would cause the eighth round of pandemic but it subsided as mysteriously as it had originated.
A group of researchers, including from India and the U.K., have studied the genome of O139 and traced the reason for its dying down after taking over from O1. They trace it to two key genomic evolutionary changes that took place in O139, the first related to the type of cholera toxin it produced and the second related to a loss of anti-microbial resistance.
This research has been published in Nature Communications.
Clinical isolates of V. cholerae O139 serogroup collected between 1993 and 2015 from several parts of India at the ICMR-National Institute of Cholera and Enteric Diseases, Kolkata and other Asian regions were included in the study.
The V. cholerae DNA were sequenced at the Wellcome Sanger Institute, U.K. and analysed at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases, U.K. and Translational Health Science and Technology Institute, Faridabad, India.
A total of 330 V. cholerae O139 isolates were included in this study. In addition, 340 genomes from published sequences were included in this study.
“When screening the genomes for the evolutionary signatures, we noticed that the antimicrobial resistant pattern was striking from wave A to wave C,” says Ankur Mutreja, a corresponding author, who is at the University of Cambridge.
“Also, since the toxin is the main virulence factor, we wanted to see if there was a particular toxin type that may have given the O139 strain some edge over the O1 strains circulating at that time,” he adds.
The study showed that the two main modifications were in the cholera toxin genes and in the antimicrobial resistance (AMR) portfolio.
“With the reduction in AMR capacity of O139, it potentially lost its competitive advantage against the O1,” says Dr. Mutreja. Another aspect comprised of the changes in the toxin gene from homogenous to heterogenous.
“This again highlights that the O139 bacterial population found it difficult to compete and thus, tried various toxin types to compete but it eventually could not compete,” he explains.
Reviving the old collection of strains, sequence analysis and interpretation of mutations and other important genes pertinent to this study were great challenges. “After getting the results from the first round of analysis, we had several rounds of discussions about the focus areas in this study,” says Thandavaranyan Ramamurthy, co-author of the paper, who is working as INSA Senior Scientist at the National Institute of Cholera and Enteric Diseases, Kolkata.
The challenge was to keep an open mind and not have preconceived notions as to why O139 was so successful in displacing O1 in the beginning and yet declined quite early. “To keep the study as transparent and as holistic as possible we ensured that we screened the comprehensive genomic data in detail without thinking of all the theories that have been previously proposed,” says Dr. Ramamurthy.
The study points to AMR as a factor that can decide the success of certain populations of bacteria that go on to produce large outbreaks of disease. Continuous surveillance is therefore necessary to monitor if any of the serotypes and serogroups are gaining antibiotic resistance over time and may become major outbreak lineages at any time.
“To stay ahead of the curve and ensure best public health outcome, it is important that vaccines and treatments are regularly re-evaluated for efficiency to any newly evolving variants,” says Dr. Ramamurthy.