Why Did a Highly Infectious Cholera Variant – Expected To Cause the 8th Cholera Pandemic – Mysteriously Die Out?

Cholera Bacteria Illustration

Cholera is a severe diarrheal illness caused by a Vibrio cholerae bacterial infection of the intestine.

A new study reveals why a particularly infectious strain of cholera declined.

A recent study explains why a highly contagious cholera bug variant that caused significant disease outbreaks in the early 1990s did not, according to expectations, create the eighth cholera pandemic. Instead, it mysteriously vanished.

The research examined samples of the cholera-causing bacterium O139 Vibrio cholerae and found that throughout time, it underwent major alterations to its genome that resulted in an unanticipated decline.

These genetic modifications led to a progressive loss of antimicrobial resistance (AMR) and a shift in the kinds of toxins generated by the cholera bug. These modifications collectively are likely responsible for O139’s failure to spark the eighth cholera pandemic.

The cholera bug is not currently being closely monitored. In order to stay ahead of the cholera bug as it evolves, scientists believe continuous monitoring of the genes responsible for AMR and toxin production is necessary. This will particularly help with the planning of vaccine improvements and suitable public health measures to stop cholera outbreaks in the future.

In 1992, the O139 variant of Vibrio cholerae was discovered for the first time in India. It swiftly surpassed the previous O1 type and caused massive disease outbreaks in India and Southern Bangladesh.

The rapid spread of O139 across Asia surprised scientists, who feared it would cause the eighth cholera pandemic – and as a result cholera vaccines were modified accordingly. But for some reason that pandemic never happened: by 2015 the variant had largely declined, and the O1 variant established itself once again as a dominant strain. Until now, scientists have not understood why.

The was recently published in Nature Communications.

“There’s a real possibility that another cholera variant may emerge with the potential to cause large outbreaks, which could lead to the eighth cholera pandemic. Continuous surveillance of the variants in circulation is our best chance of preventing mass outbreaks,” said Dr. Ankur Mutreja, in the University of Cambridge’s Institute of Therapeutic Immunology and Infectious Disease, senior author of the study.

Cholera is a life-threatening infectious disease, usually caught by eating or drinking contaminated food or water. It only causes large outbreaks in places where hygiene and sanitation are poor, so it is primarily restricted to the developing world.

Cholera can also arise when water and sewage systems are disrupted due to war or natural disasters. Recent news reports have warned that the Ukrainian city of Mariupol, all but destroyed by weeks of Russian shelling, is now at risk of a major cholera outbreak.

In the past 200 years, seven cholera pandemics have killed millions of people across the world; the seventh is still ongoing with large outbreaks in Yemen and Somalia. The dominant variant of Vibrio cholerae, the bacteria that causes cholera outbreaks today, is called O1 and arose in the 1960s – replacing all pre-existing variants.

The new study analyzed 330 samples of the cholera variant O139, taken between 1992 and 2015, to reveal two key changes in its genome that may have been the cause of its decline over three overlapping waves of disease transmission.

Before the O139 variant appeared, cholera was sensitive to many antibiotics. But O139 was resistant to these, which is likely to be the reason it became the dominant variant very quickly.

The study found that O139 had started out with several genes giving it resistance to antibiotics. But over time it gradually lost these genes. In tandem, the O1 variant gained antibiotic resistance.

“When it first arose, the O139 variant of cholera had antimicrobial resistance. But over time this resistance was lost — while the pre-existing O1 variant gained resistance and re-established itself,” said Mutreja.

The World Health Organization (WHO) estimates that globally there are 1.3 to 4.0 million cases of cholera, with 21,000 to 143,000 deaths, every year. There have been seven pandemics of cholera, all of which have been caused by the O1 variant of Vibrio cholerae, with the first one documented in 1817.

Reference: “Vibrio cholerae O139 genomes provide a clue to why it may have failed to usher in the eighth cholera pandemic” by Thandavarayan Ramamurthy, Agila Kumari Pragasam, Alyce Taylor-Brown, Robert C. Will, Karthick Vasudevan, Bhabatosh Das, Sunil Kumar Srivastava, Goutam Chowdhury, Asish K. Mukhopadhyay, Shanta Dutta, Balaji Veeraraghavan, Nicholas R. Thomson, Naresh C. Sharma, Gopinath Balakrish Nair, Yoshifumi Takeda, Amit Ghosh, Gordon Dougan and Ankur Mutreja, 5 July 2022, Nature Communications.
DOI: 10.1038/s41467-022-31391-4

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