skip to content

Faculty of Biology

 

Ability of multi-drug resistant infection to evolve within cystic fibrosis patients highlights need for rapid treatment

Thu, 29/04/2021 - 19:00

Around one in 2,500 children in the UK is born with cystic fibrosis, a hereditary condition that causes the lungs to become clogged up with thick, sticky mucus. The condition tends to decrease life expectancy among patients.

In recent years, M. abscessus, a species of multi-drug resistant bacteria, has emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause a severe pneumonia leading to accelerated inflammatory damage to the lungs, and may prevent safe lung transplantation. It is also extremely difficult to treat – fewer than one in three cases is treated successfully.

In a study published today in Science, a team led by scientists at the University of Cambridge examined whole genome data for 1,173 clinical M. abscessus samples taken from 526 patients to study how the organism has evolved – and continues to evolve. The samples were obtained from cystic fibrosis clinics in the UK, as well as centres in Europe, the USA and Australia.

The team found two key processes that play an important part in the organism’s evolution. The first is known as horizontal gene transfer – a process whereby the bacteria pick up genes or sections of DNA from other bacteria in the environment. Unlike classical evolution, which is a slow, incremental process, horizontal gene transfer can lead to big jumps in the pathogen’s evolution, potentially allowing it to become suddenly much more virulent.

The second process is within-host evolution. As a consequence of the shape of the lung, multiple versions of the bacteria can evolve in parallel – and the longer the infection exists, the more opportunities they have to evolve, with the fittest variants eventually winning out. Similar phenomena have been seen in the evolution of new SARS-CoV-2 variants in immunocompromised patients.

Professor Andres Floto, joint senior author from the Centre for AI in Medicine (CCAIM) and the Department of Medicine at the University of Cambridge and the Cambridge Centre for Lung Infection at Royal Papworth Hospital, said: “What you end up with is parallel evolution in different parts of an individual’s lung. This offers bacteria the opportunity for multiple rolls of the dice until they find the most successful mutations. The net result is a very effective way of generating adaptations to the host and increasing virulence. 

“This suggests that you might need to treat the infection as soon as it is identified. At the moment, because the drugs can cause unpleasant side effects and have to be administered over a long period of time – often as long as 18 months – doctors usually wait to see if the bacteria cause illness before treating the infection. But what this does is give the bug plenty of time to evolve repeatedly, potentially making it more difficult to treat.”

Professor Floto and colleagues have previously advocated routine surveillance of cystic fibrosis patients to check for asymptomatic infection. This would involve patients submitting sputum samples three or four times a year to check for the presence of M. abscessus infection. Such surveillance is carried out routinely in many centres in the UK.

Using mathematical models, the team have been able to step backwards through the organism’s evolution in a single individual and recreate its trajectory, looking for key mutations in each organism in each part of the lung. By comparing samples from multiple patients, they were then able to identify the key set of genes that enabled this organism to change into a potentially deadly pathogen.

These adaptations can occur very quickly, but the team found that their ability to transmit between patients was constrained: paradoxically, those mutations that allowed the organism to become a more successful pathogen within the patient also reduced its ability to survive on external surfaces and in the air – the key mechanisms by which it is thought to transmit between people. 

Potentially one of the most important genetic changes witnessed by the team was one that contributed towards M. abscessus becoming resistant to nitric oxide, a compound naturally produced by the human immune system. The team will shortly begin a clinical trial aimed at boosting nitric oxide in patients’ lung by using inhaled acidified nitrite, which they hope would become a novel treatment for the devastating infection.

Examining the DNA taken from patient samples is also important in helping understand routes of transmission. Such techniques are used routinely in Cambridge hospitals to map the spread of infections such as MRSA and C. difficile – and more recently, SARS-CoV-2. Insights into the spread of M. abscessus helped inform the design of the new Royal Papworth Hospital building, opened in 2019, which has a state-of-the-art ventilation system to prevent transmission. The team recently published a study showing that this ventilation system was highly effective at reducing the amount of bacteria in the air.

Professor Julian Parkhill, joint senior author from the Department of Veterinary Medicine at the University of Cambridge, added: “M. abscessus can be a very challenging infection to treat and can be very dangerous to people living with cystic fibrosis, but we hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new pathogenic variants.”

The team have used their research to develop insights into the evolution of M. tuberculosis – the pathogen that causes TB about 5,000 years ago. In a similar way to M. abscessus, M. tuberculosis likely started life as an environmental organism, acquired genes by horizontal transfer that made particular clones more virulent, and then evolved through multiple rounds of within-host evolution. While M. abscessus is currently stopped at this evolutionary point, M. tuberculosis evolved further to be able to jump directly from one person to another.  

Dr Lucy Allen, Director of Research at the Cystic Fibrosis Trust, said: “This exciting research brings real hope of better ways to treat lung infections that are resistant to other drugs. Our co-funded Innovation Hub with the University of Cambridge really shows the power of bringing together world-leading expertise to tackle a health priority identified by people with cystic fibrosis. We’re expecting to see further impressive results in the future coming from our joint partnership.”

The study was funded by the Wellcome Trust, Cystic Fibrosis Trust, NIHR Cambridge Biomedical Research Centre and Fondation Botnar.

Reference
Bryant, JM et al. Stepwise pathogenic evolution of Mycobacterium abscessus. Science; 30 Apr 2021

Scientists have been able to track how a multi-drug resistant organism is able to evolve and spread widely among cystic fibrosis patients – showing that it can evolve rapidly within an individual during chronic infection. The researchers say their findings highlight the need to treat patients with Mycobacterium abscessus infection immediately, counter to current medical practice.

cystic fibrosisevolutiondrug resistanceAndres FlotoJulian ParkhillCystic Fibrosis TrustWellcome Sanger InstituteWellcomeNIHR Cambridge Biomedical Research CentreFondation BotnarSchool of Clinical MedicineDepartment of MedicineDepartment of Veterinary MedicineCambridge Centre for AI in MedicineSchool of the Biological SciencesWe hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new pathogenic variantsJulian ParkhillJon SneddonPatient with cystic fibrosis


The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified.  All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

YesNews type: News

The Kennel Club Genetics Centre to re-open as part of the University of Cambridge

Tue, 23/03/2021 - 17:15

The Kennel Club Charitable Trust has funded the centre since its initial launch at the Animal Health Trust in 2009. The new centre will continue to be led by Dr Cathryn Mellersh, and will resume its mission to develop DNA tests and breeding tools for some of the most common and debilitating inherited conditions in dogs. 

Professor James Wood, Head of the Department of Veterinary Medicine at the University of Cambridge, said: “We are delighted that the important work by Cathryn and her team, funded by The Kennel Club Charitable Trust, can now continue through the Canine Genetics Centre at Cambridge Vet School. We look forward to working together for the health and welfare of our much loved canines.”

The Kennel Club and the canine genetics team will work together to ensure that the centre’s research targets conditions that have the greatest impact on the health of dogs. The Kennel Club’s breed health and conservation plans, a project that gathers all available health information and data about each breed, will play a vital role in guiding the centre’s objectives and areas of research.  

During its time at the Animal Health Trust, The Kennel Club Canine Genetics Centre had a significant impact on the health of numerous breeds. Researchers at the centre developed 25 different DNA tests for canine inherited diseases that affect over 50 breeds. Research into the impact of some of these tests revealed that over a ten year period, thanks to uptake of these tests by responsible breeders, the frequency of disease-causing genetic variants in some breeds reduced by a staggering 90%. 

Close collaboration with breed clubs and breeders is essential to the success of the centre, as is the collection of over 40,000 DNA samples that has been developed over the last 20 years. These samples, along with valuable scientific and DNA sequence data, have now been secured and transferred to the University of Cambridge for further analysis.

Dr Cathryn Mellersh, head of The Kennel Club Genetics Centre said: “The last ten years have been incredibly important to dog health and, thanks to the University of Cambridge, especially Professor James Wood for all his assistance in safeguarding our resources and The Kennel Club Charitable Trust, this work can now continue. Our work to support breeders in reducing health problems in dogs is essential and we are eager to continue this important work and are thankful to everyone for their support.”

Further information regarding The Kennel Club’s extensive work in the field of canine health and research can be found on The Kennel Club website.

Adapted from a press release by The Kennel Club.

Following the announcement in July 2020 of the closure of the Animal Health Trust, The Kennel Club Canine Genetics Centre will officially re-open and be located at the University of Cambridge where its vital research into dog genetics and inherited canine conditions can continue.  

James WoodThe Kennel ClubDepartment of Veterinary MedicineSchool of the Biological SciencesWe look forward to working together for the health and welfare of our much loved canines.James WoodSyed Ahmad on UnsplashDog


The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified.  All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

YesLicense type: AttributionNews type: News

Study highlights ‘unbridled globetrotting’ of the strangles pathogen in horses

Tue, 09/03/2021 - 09:32

The results, published today in the journal Microbial Genomics, provide evidence of the important role played by the movement of horses in spreading this disease, providing new opportunities for interventions that will prevent future outbreaks.

Strangles, caused by the bacteria Streptococcus equi, is the most frequently diagnosed infectious disease of horses, with 600 outbreaks estimated to occur in the United Kingdom each year.

Streptococcus equi invades the lymph nodes of head and neck of horses, causing them to swell and form abscesses that can, in around 2% of cases, literally strangle the horse to death. Some of the horses that recover from strangles remain persistently infected. These apparently healthy animals shed bacteria into the environment and spread the disease to other horses that they come into contact with.

Using standard diagnostic testing, the Streptococcus equi strains look almost identical. But by carefully examining the DNA of the bacteria, the team were able to track different variants as they spread across the world.

The research used the new online Pathogenwatch resource, developed at the Wellcome Sanger Institute, to visualise and share genome data to track the course of infections.

“Piecing the puzzle together, we showed that cases in Argentina, the United Kingdom and the United Arab Emirates were closely linked. Along with other examples, we provide evidence that the global trade and movement of horses is helping to spread the disease,” said Professor Matthew Holden of the University of St Andrews, who was involved in the study.

"This study shows once again the power of genomic data to uncover the fine detail of pathogen transmission locally and globally,” said Professor Julian Parkhill in the University of Cambridge’s Department of Veterinary Medicine, who was involved in the study.

He added: “Using whole genome sequences we can track the movement of pathogens with very high precision, showing how and where to intervene to prevent the disease spreading."

Strangles was first described in Medieval times and, with the exception of Iceland, affects horses in all corners of the world. The freedom from this disease enjoyed by Iceland is by virtue of a ban on the import of horses, which has been in place for over 1,000 years.

“This has been an incredible team effort, which was only possible through the collaboration of leading researchers from twenty-nine different scientific institutes in eighteen countries” said Dr Andrew Waller of Intervacc AB.

Horses are transported all over the world as they move to new premises or attend competitions and events. New cases of Strangles can be prevented by treating carriers before they pass on the bacteria.

Reference

Mitchell, C. et al. 'Globetrotting strangles: the unbridled national and international transmission of Streptococcus equi between horses.' Microbial Genomics, March 2021.

 

Collaborating Institutes

Argentina: Clinica Equina, Buenos Aires

Australia: University of Melbourne

Belgium: Ghent University, Merelbeke

France: LABÉO Frank Duncombe, Caen

Germany: Labor Dr. Böse GmbH, Harsum

Ireland: Irish Equine Centre, Naas; University College Dublin

Israel: Kimron Veterinary Institute, Bet Dagan

Italy: University of Camerino

Japan: Japan Racing Association, Tochigi

Poland: Institute of Veterinary Medicine, Warsaw University of Life Sciences - SGGW

New Zealand: Massey University, Palmerston North; University of Waikato, Hamilton

Saudi Arabia: Al Khalediah Equine Hospital, Riyadh

Spain: Exopol, Zaragoza; Universidad Complutense, Madrid

Sweden: Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala; Intervacc AB, Stockholm

The Netherlands: Royal GD, Deventer

United Arab Emirates: Central Veterinary Research Laboratory, Dubai; Emirates Racing Authority, Dubai

United Kingdom: Animal Health Trust, Newmarket; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford; Centre for Genomic Pathogen Surveillance, Wellcome Trust Sanger Institute, Cambridge; Redwings Horse Sanctuary; University of Cambridge; University of St Andrews

United States of America: Gluck Equine Research Center, Lexington; Weatherford Equine Medical Centre, Texas

 

Adapted from a press release by Intervacc.

In the largest ever study of its kind into an equine pathogen, scientists in 18 countries used the latest DNA sequencing techniques to track the bacteria responsible for a disease called 'strangles’ in horses around the world.

Infectious diseasesJulian ParkhillUniversity of St AndrewsIntervacc ABDepartment of Veterinary MedicineSchool of the Biological SciencesCambridge Infectious DiseasesUsing whole genome sequences we can track the movement of pathogens with very high precision, showing how and where to intervene to prevent the disease spreading.Julian Parkhill Nicky on PixabayHorse


The text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified.  All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

YesLicense type: AttributionNews type: News