̽��ֱ�� of Cambridge - Gordon Dougan

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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DNA test can quickly identify pneumonia in patients with severe COVID-19, aiding faster treatment

sc604 — Fri, 15 Jan 2021 06:00:00 +0000

For patients with the most severe forms of COVID-19, mechanical ventilation is often the only way to keep them alive, as doctors use anti-inflammatory therapies to treat their inflamed lungs. However, these patients are susceptible to further infections from bacteria and fungi that they may acquire while in hospital – so called ‘ventilator-associated pneumonia’.

Now, a team of scientists and doctors at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, led by Professor Gordon Dougan, Dr Vilas Navapurkar and Dr Andrew Conway Morris, have developed a simple DNA test to quickly identify these infections and target antibiotic treatment as needed.

̽��ֱ��test, developed at Addenbrooke’s hospital in collaboration with Public Health England, gives doctors the information they need to start treatment within hours rather than days, fine-tuning treatment as required and reducing the inappropriate use of antibiotics. This approach, based on higher throughput DNA testing, is being rolled out at Cambridge ̽��ֱ�� Hospitals and offers a route towards better treatments for infection more generally. ̽��ֱ��results are reported in the journal Critical Care.

Patients who need mechanical ventilation are at significant risk of developing secondary pneumonia while they are in intensive care. These infections are often caused by antibiotic-resistant bacteria, and are hard to diagnose and need targeted treatment.

“Early on in the pandemic we noticed that COVID-19 patients appeared to be particularly at risk of developing secondary pneumonia, and started using a rapid diagnostic test that we had developed for just such a situation,” said co-author Dr Andrew Conway Morris from Cambridge’s Department of Medicine and an intensive care consultant. “Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit.”

COVID-19 patients are thought to be at increased risk of infection for several reasons. Due to the amount of lung damage, these severe COVID-19 cases tend to spend more time on a ventilator than patients without COVID-19. In addition, many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs, but also have impaired anti-microbial functions, increasing the risk of infection.

Normally, confirming a pneumonia diagnosis is challenging, as bacterial samples from patients need to be cultured and grown in a lab, which is time-consuming. ̽��ֱ��Cambridge test takes an alternative approach by detecting the DNA of different pathogens, which allows for faster and more accurate testing.

̽��ֱ��test uses multiple polymerase chain reaction (PCR) which detects the DNA of the bacteria and can be done in around four hours, meaning there is no need to wait for the bacteria to grow. “Often, patients have already started to receive antobiotics before the bacteria have had time to grow in the lab,” said Morris. “This means that results from cultures are often negative, whereas PCR doesn’t need viable bacteria to detect – making this a more accurate test.”

̽��ֱ��test – which was developed with Dr Martin Curran, a specialist in PCR diagnostics from Public Health England’s Cambridge laboratory – runs multiple PCR reactions in parallel, and can simultaneously pick up 52 different pathogens, which often infect the lungs of patients in intensive care. At the same time, it can also test for antibiotic resistance.

“We found that although patients with COVID-19 were more likely to develop secondary pneumonia, the bacteria that caused these infections were similar to those in ICU patients without COVID-19,” said lead author Mailis Maes, also from the Department of Medicine. “This means that standard antibiotic protocols can be applied to COVID-19 patients.”

This is one of the first times that this technology has been used in routine clinical practice and has now been approved by the hospital. ̽��ֱ��researchers anticipate that similar approaches would benefit patients if used more broadly.

This study was funded by the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference:
Mailis Maes et al. ‘Ventilator-associated pneumonia in critically ill patients with COVID-19.’ Critical Care (2021). DOI: 10.1186/s13054-021-03460-5

Researchers have developed a DNA test to quickly identify secondary infections in COVID-19 patients, who have double the risk of developing pneumonia while on ventilation than non-COVID-19 patients.

Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit

Andrew Conway Morris

Official U.S. Navy Page

Lt. Cmdr. Michael Heimes checks on a patient connected to a ventilator at Baton Rouge General Mid City campus

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“We’re in it for the long haul”

cjb250 — Wed, 21 Oct 2020 07:46:34 +0000

In late 2019, a new institute opened on the Cambridge Biomedical Campus. Its timing could not have been better - as the COVID-19 pandemic sent Britain into lockdown several months later, the institute found itself at the heart of the ̽��ֱ��’s response to this unprecedented challenge.

COVID-19: What to expect from a vaccine

cjb250 — Fri, 11 Sep 2020 10:31:56 +0000

Vaccine expert Professor Gordon Dougan looks at the challenges of developing and delivering a vaccine against COVID-19.

Tackling COVID-19: Professor Gordon Dougan

jg533 — Thu, 16 Jul 2020 07:00:29 +0000

This article is part of a series in which we speak to some of the many Cambridge researchers tackling COVID-19. For other articles about our latest COVID-19-related research, click here.

I run a lab in the Jeffrey Cheah Biomedical Centre (JCBC) on the Cambridge Biomedical Campus, where we study antibiotic resistance and infections. We work closely with Cambridge ̽��ֱ�� Hospitals (CUH), applying genomics to analyse clinical samples. I’m also a strategic advisor to Wellcome, and until recently was spending two days a week at its headquarters in London. I’m now spending all my working time in the JCBC, continuing to work remotely for Wellcome. I’ve worked throughout the lockdown.

My team was involved in setting up COVID-19 testing for healthcare workers, and establishing a containment level 3 facility (designed to safely handle infectious diseases) for this. It was hard work, but I believe it made a major impact on reducing COVID in the hospital and department so it has been very rewarding. ̽��ֱ��group is now slowly stepping back from testing and returning to our normal work.

I also helped establish the COVID-19 Genomics UK (COG-UK) Consortium for sequencing the virus, together with the Principal Investigator Sharon Peacock. I did a lot of the organisational work, including setting up the grant with the ̽��ֱ��. This was all done at very short notice. Ian Goodfellow is head of sequencing for Cambridge COG-UK, and has been great at linking with the hospital. We also helped out with the Intensive Care Unit at the peak of the pandemic, looking for secondary infections and antibiotic resistance.

My lab works on the molecular mechanisms involved in infection and resistance to treatments. We use simple models of infection, mostly based around high throughput genomic assays and models based on human stem cells. I also have global connections for my work on typhoid - multiple field sites around the world managed partly through joint funding with the International Vaccine Institute from Gates, EU, and Wellcome. We run projects working on maximising the amount of useful data returned on the analysis of samples, both on these sites and within the Cambridge hospital system.

I’ve been working on epidemics all my life, so in some ways I’ve just carried on as normal. I have always been very careful about things like social distancing and hand-washing when traveling in epidemic areas, so this is quite natural for me and my team. I think it’s now a psychological battle to get back to normality. In many parts of the world people still live on a daily basis with diseases like cholera, typhoid and malaria.

̽��ֱ��UK infrastructure was absolutely not ready for COVID-19. We need to learn to adapt and be ready for the next epidemic, because if we carry on the way we are there will be another one and it could be a lot worse, for example by affecting children - who are largely spared by COVID-19.

̽��ֱ��research community’s response to COVID-19 could have been better. Obviously the lockdown has meant that it’s very difficult to find people to get anything done. Some people have stepped up and been excellent; others have struggled. We need to learn from this: the multiple levels of administration within organisations need to be simplified. Ironically during the pandemic we were more or less left to get on with things and I’m sure that helped us.

We need a much better local infrastructure both within hospitals and the community. For example, track and test cannot be invented during an epidemic; it has to be in place already. ̽��ֱ��clinicians, scientists and management within CUH have been fantastic in my opinion, but we need the infrastructure to match. We now have excellent facilities coming online in the JCBC but we need more. We need to re-establish health clinics in the community, and get GPs out of their offices and back out there (this is absolutely not a criticism of GPs, I am sure they would agree!).

When the pandemic is over I’m looking forward to going on holiday and having a meal out with my wife…..and watching Scunthorpe United.

Gordon Dougan FRS is an expert on vaccines and genomics whose distinguished career has included contribution to the development of several vaccines. He is a Professor at the Cambridge Institute for Therapeutic Immunology & Infectious Disease (CITIID) in the Department of Medicine, and is involved in the new Wolfson Interdisciplinary Research Hub in Global Health. He recently wrote a blog on How we lost our collective memory of epidemics.

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“In many parts of the world people still live with the daily threat of diseases like cholera, typhoid, and malaria. In reality COVID is just another infection,” says Professor Gordon Dougan.

Professor Gordon Dougan

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150 scientists from new institute join Cambridge fight against COVID-19

cjb250 — Wed, 08 Apr 2020 16:12:03 +0000

Based on the Cambridge Biomedical Campus, the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) is integrated with the NHS both locally, through Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust and the Royal Papworth Hospital NHS Foundation Trust, and nationally, in particular through the National Institute for Health Research (NIHR) BioResource.

CITIID, based in the Jeffrey Cheah Biomedical Centre, opened its doors in September 2019. Following the outbreak of SARS-CoV-2, the virus that causes COVID-19, the institute has redirected all of its research efforts to tackling the pandemic.

“ ̽��ֱ��world is facing an unprecedented challenge, with potentially millions of lives at risk, which is why over 150 of my colleagues at our new institute are focusing their expertise on the fightback against COVID-19,” says Professor Ken Smith, Director of CITIID.

“Together with our partners in the NHS and NIHR, we aim to identify those patients at greatest risk and understand why the coronavirus makes some people so sick while leaving others with only mild symptoms. Ultimately, we hope this will lead to the development of new treatments against this dreadful disease.”

̽��ֱ��Institute last week opened what is believed to be the largest Containment Level 3 Facility in any UK academic institution. These facilities are required for work on dangerous pathogens such as the coronavirus.

“ ̽��ֱ��state-of-the-art facilities and equipment at CITIID will allow us to do essential work on the novel coronavirus in a safe environment,” says Professor Gordon Dougan. “Our institute, positioned as it is on the thriving Cambridge Biomedical Campus, is perfectly suited to lead Cambridge’s response, working with research and health partners locally, nationally and internationally on this urgent problem.”

̽��ֱ��team at the institute has also been instrumental in evaluating and helping set up point-of-care, rapid diagnostic testing for patients at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals (CUH) NHS Foundation Trust, as well as developing tests for frontline healthcare workers treating COVID-19 patients.

“Organising the logistics for testing has been a huge challenge,” says Professor Paul Lehner. “But thanks to a tremendous collaborative effort between CUH and the ̽��ֱ��, we are now testing frontline healthcare workers as well as people who are off work and in isolation due to potential COVID-related contacts.”

Recruitment is already underway of COVID-19 patients at Addenbrooke’s. Researchers aim to recruit all consenting patients infected with SARS-CoV-2 from the hospital.

Once consent has been obtained from a patient, the team will take blood and other samples, which will be processed in the Department of Medicine’s laboratories before being transferred for storage and further study at CITIID. Samples will be taken when the patients first arrive at the hospital and during the course of disease, with the research team also working alongside NHS staff to support patient care.

This study forms part of the COVID-19 BioResource, a collaboration with the NIHR BioResource, and will involve state-of-the-art analysis of the samples, helping the team understand how coronavirus infects us and causes disease and how our immune system fights back. It aims to allow researchers to predict which patients will do well or badly, and to help inform the development of new medicines to tackle the disease.

“A key challenge for the institute is trying to understand how much of the lung disease seen in COVID-19 patients is caused by the virus itself and how much is due to an inappropriate immune response,” explains Professor Lehner. “An answer to this question will help guide how best we treat this devastating condition.”

̽��ֱ�� ̽��ֱ�� recently announced that CITIID would take be taking a leading role in the £20 million COVID-19 Genomics UK Consortium, a major national effort to help understand and control the infection. Its researchers are also leading the evaluation of a new rapid diagnostic test for COVID-19, developed by a ̽��ֱ�� spinout company, which is capable of diagnosing the infection in under 90 minutes.

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One of Cambridge’s newest institutes, established to study the relationship between infectious disease and our immune systems, is leading the ̽��ֱ�� of Cambridge’s response to the COVID-19 pandemic, with over 150 scientists and clinicians, the UK’s largest academic Containment Level 3 Facility, and a range of collaborators from across the UK and beyond.

̽��ֱ��world is facing an unprecedented challenge, with potentially millions of lives at risk, which is why over 150 of my colleagues at our new institute are focusing their expertise on the fightback against COVID-19

Ken Smith

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Opinion: How we lost our collective memory of epidemics

cjb250 — Tue, 31 Mar 2020 07:41:03 +0000

Over the past 70 years richer nations have gradually lost their sense of danger concerning epidemics and serious infections, writes Professor Gordon Dougan. We must now reacquire this instinctive memory.