̽��ֱ�� of Cambridge - Ankur Mutreja

Study reveals why highly infectious cholera variant mysteriously died out

jg533 — Tue, 05 Jul 2022 14:55:32 +0000

A new study reveals why a highly infectious variant of the cholera bug, which caused large disease outbreaks in the early 1990s, did not cause the eighth cholera pandemic as feared – but instead unexpectedly disappeared.

̽��ֱ��study analysed samples of O139 Vibrio cholerae, a variant of the bacteria that causes cholera, and discovered significant changes in its genome over time that led to its unexpected decline.

These genetic changes resulted in a gradual loss of antimicrobial resistance (AMR), and a change in the types of toxin produced by the cholera bug. In combination, these changes are likely to account for O139’s failure to seed the eighth cholera pandemic.

̽��ֱ��cholera bug is not currently monitored on a regular basis. Scientists say continuous monitoring of the genes underlying AMR and toxin production is key to keeping ahead of the cholera bug as it evolves. In particular, this will help to plan changes to vaccines and appropriate public health responses to prevent future cholera outbreaks.

̽��ֱ��O139 variant of Vibrio cholerae was first detected in India in 1992. It quickly became dominant over the existing O1 variant and caused huge disease outbreaks in India and Southern Bangladesh.

̽��ֱ��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.

̽��ֱ��study is published today in the journal 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 ̽��ֱ�� 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 is poor, so is mainly restricted to the developing world.

Cholera can also arise when water and sewage systems are disrupted due to war or natural disaster. 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. ̽��ֱ��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.

̽��ֱ��new study analysed 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.

̽��ֱ��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.

̽��ֱ��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 O1 variant of Vibrio cholerae, with the first one documented in 1817.

This research was funded by the NIHR Cambridge Biomedical Research Centre.

Reference

Ramamurthy, T et al. ‘Vibrio cholerae O139 genomes provide a clue to why it may have failed to usher in the eighth cholera pandemic.’ Nature Communications, July 2022. DOI: 10.1038/s41467-022-31391-4

Scientists say continuous monitoring of the cholera bug genome is key to preventing outbreaks of new variants.

There’s a real possibility that another cholera variant may emerge with the potential to cause large outbreaks

Ankur Mutreja

kozorog on iStock/Getty

Water sample in test tube

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Diphtheria risks becoming ‘major global threat’ again as it evolves resistance to antimicrobials

cjb250 — Mon, 08 Mar 2021 11:07:29 +0000

̽��ֱ��researchers, led by scientists at the ̽��ֱ�� of Cambridge, say that the impact of COVID-19 on diphtheria vaccination schedules, coupled with a rise in the number of infections, risk the disease once more becoming a major global threat.

Diphtheria is a highly contagious infection that can affect the nose and throat, and sometimes the skin. If left untreated it can prove fatal. In the UK and other high-income countries, babies are vaccinated against infection. However, in low- and middle-income countries, the disease can still cause sporadic infections or outbreaks in unvaccinated and partially-vaccinated communities.

̽��ֱ��number of diphtheria cases reported globally has being increasing gradually. In 2018, there were 16,651 reported cases, more than double the yearly average for 1996–2017 (8,105 cases).

Diphtheria is primarily caused by the bacterium Corynebacterium diphtheriae and is mainly spread by coughs and sneezes, or through close contact with someone who is infected. In most cases, the bacteria cause acute infections, driven by the diphtheria toxin – the key target of the vaccine. However, non-toxigenic C. diphtheria can also cause disease, often in the form of systemic infections.

In a study published today in Nature Communications, an international team of researchers from the UK and India used genomics to map infections, including a subset from India, where over half of the globally reported cases occurred in 2018.

By analysing the genomes of 61 bacteria isolated from patients and combining these with 441 publicly available genomes, the researchers were able to build a phylogenetic tree – a genetic ‘family tree’ – to see how the infections are related and understand how they spread. They also used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation.

̽��ֱ��researchers found clusters to genetically-similar bacteria isolated from multiple continents, most commonly Asia and Europe. This indicates that C. diphtheriae has been established in the human population for at least over a century, spreading across the globe as populations migrated.

̽��ֱ��main disease-causing component of C. diphtheriae is the diphtheria toxin, which is encoded by the tox gene. It is this component that is targeted by vaccines. In total, the researchers found 18 different variants of the tox gene, of which several had the potential to change the structure of the toxin.

Professor Gordon Dougan from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) said: ““ ̽��ֱ��diphtheria vaccine is designed to neutralise the toxin, so any genetic variants that change the toxin’s structure could have an impact on how effective the vaccine is. While our data doesn’t suggest the currently used vaccine will be ineffective, the fact that we are seeing an ever-increasing diversity of tox variants suggests that the vaccine, and treatments that target the toxin, need to be appraised on a regular basis.”

Diphtheria infections can usually be treated with a number of classes of antibiotic. While C. diphtheriae resistant to antibiotics have been reported, the extent of such resistance remains largely unknown.

When the team looked for genes that might confer some degree of resistance to antimicrobials, they found that the average number of AMR genes per genome was increasing each decade. Genomes of bacteria isolated from infections from the most recent decade (2010-19) showed the highest average number of AMR genes per genome, almost four times as many on average than in the next highest decade, the 1990s.

Robert Will, a PhD student at CITIID and the study’s first author, said: “ ̽��ֱ��C. diphtheriae genome is complex and incredibly diverse. It’s acquiring resistance to antibiotics that are not even clinically used in the treatment of diphtheria. There must be other factors at play, such as asymptomatic infection and exposure to a plethora of antibiotics meant for treating other diseases.”

Erythromycin and penicillin are the traditionally recommended antibiotics of choice for treating confirmed cases of early-stage diphtheria, though there are several different classes of antibiotics available to treat the infection. ̽��ֱ��team identified variants resistant to six of these classes in isolates from the 2010s, higher than in any other decades.

Dr Pankaj Bhatnagar from the World Health Organization country office for India said: “AMR has rarely been considered as a major problem in the treatment of diphtheria, but in some parts of the world, the bacterial genomes are acquiring resistance to numerous classes of antibiotics. There are likely to be a number of reasons to this, including exposure of the bacteria to antibiotics in their environment or in asymptomatic patients being treated against other infections.”

̽��ֱ��researchers say that COVID-19 has had a negative impact on childhood vaccination schedules worldwide and comes at a time when reported case numbers are rising, with 2018 showing the highest incidence in 22 years.

Dr Ankur Mutreja from CITIID, who led the study, said: “It’s more important than ever that we understand how diphtheria is evolving and spreading. Genome sequencing gives us a powerful tool for observing this in real time, allowing public health agencies to take action before it’s too late.

“We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form.”

̽��ֱ��research was funded primarily by the Medical Research Council, with additional support from the NIHR Cambridge Biomedical Research Centre.

Reference
Will, RC et al. Spatiotemporal persistence of multiple, diverse clades and toxins of Corynebacterium diphtheria. Nat Comms; 8 Mar 2021; DOI: 10.1038/s41467-021-21870-5

Diphtheria – a relatively easily-preventable infection – is evolving to become resistant to a number of classes of antibiotics and in future could lead to vaccine escape, warn researchers from the UK and India.

We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form

Ankur Mutreja

DFID - UK Department for International Development

UK Emergency Medical Team paediatric nurse checks a girl for symptoms of Diphtheria in the Kutapalong refugee camp, Bangladesh

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