Multidrug-resistant infections that are about to evolve in patients with cystic fibrosis

Finger clubbing is a classic feature of cystic fibrosis, but it is not found in many patients. Credits: Jerry Nick, MD / Wikipedia

Scientists have been able to track how multidrug-resistant strains can evolve and spread widely among patients with cystic fibrosis. This indicates that it can evolve rapidly within an individual during a chronic infection.Researchers say their findings highlight the need to treat patients Mycobacterium absesus It quickly becomes infected and goes against current medical practice.

In the UK, 1 in 2,500 children are born with cystic fibrosis. Cystic fibrosis is a hereditary disorder in which the lungs are thick and clogged with mucus. This condition tends to shorten the patient’s life expectancy.

in recent years, M. AbsesasA type of multidrug-resistant strain has emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause severe pneumonia, accelerate inflammatory damage to the lungs, and prevent safe lung transplants. Also, treatment is very difficult. Less than 1 in 3 cases will be treated normally.

In the study published today Science, A team led by scientists at the University of Cambridge examined 1,173 clinical whole-genome data M. Absesas Samples taken from 526 patients to study how the organism evolved and continues to evolve. Samples were obtained from the Cystic Fibrosis Clinic in the United Kingdom and centers in Europe, the United States and Australia.

The team has discovered two important processes that play important roles in the evolution of living things. The first is known as horizontal gene transfer. This is the process by which a bacterium picks up a section of a gene or DNA from another bacterium in the environment. Unlike classical evolution, which is a slow, gradual process, horizontal gene transfer can lead to major jumps in the evolution of pathogens, which can suddenly become much more toxic.

The second process is evolution within the host. As a result of the shape of the lungs, multiple versions of the bacterium can evolve in parallel. The longer the infection, the more chances it has to evolve, and ultimately the most appropriate mutant wins. A similar phenomenon is seen in the evolution of new SARS-CoV-2 mutants in immunocompromised patients.

Professor Andres Floto, co-senior author of the Cambridge University School of Medicine, the University of Cambridge School of Medicine and the Cambridge Lung Infection Center at the Royal Papworth Hospital, said: This gives the bacterium the opportunity to roll the dice multiple times until the most successful mutation is found. The end result is a very effective way of creating adaptation to the host and increasing toxicity.

“This suggests that the infection may need to be treated as soon as it is identified. At this time, the drug can cause unpleasant side effects and is long-term (often 18 months). This is because it needs to be administered over). Usually, the infection is treated after checking if the bacteria cause the disease, but this gives enough time for the bug to evolve repeatedly. Treatment can be more difficult. “

Professor Floto and colleagues have previously advocated regular surveillance of patients with cystic fibrosis to check for asymptomatic infections. For this, the patient submits sputum samples 3-4 times a year, M. Absesas infection. Such surveillance is routinely carried out at many centers in the United Kingdom.

Using a mathematical model, the team was able to recede the evolution of an organism in a single individual and recreate its trajectory to look for important mutations in each organism in each part of the lung. By comparing samples from multiple patients, they were able to identify an important set of genes that allowed the organism to transform into a potentially deadly pathogen.

Although these indications can occur very quickly, the team found that their ability to communicate between patients was limited. Paradoxically, mutations that allow an organism to become a more successful pathogen within a patient are external and air—the main mechanism by which it is believed to be transmitted between people.

One of the most important genetic changes the team has witnessed is M. Absesas It becomes resistant to nitric oxide, a compound naturally produced by the human immune system. The team will soon begin clinical trials aimed at boosting nitric oxide in the lungs of patients using inhaled acidic nitrite. We hope this will be a new remedy for catastrophic infections.

Examining the DNA taken from a patient’s sample is also important in understanding the route of infection. Such techniques are routinely used in Cambridge hospitals to map the spread of infections such as MRSA, C. difficile, and more recently SARS-CoV-2.Insight into the spread of M. Absesas It helped inform the design of the new Royal Papworth Hospital building, which opened in 2019. The building has a state-of-the-art ventilation system to prevent infection. The team recently published a study showing that this ventilation system is very effective in reducing the amount of bacteria in the air.

Professor Julian Parkhill, co-senior author of the University of Cambridge School of Veterinary Medicine, added:M. Absesas Although it is a very difficult infection to treat and can be very dangerous for people with cystic fibrosis, the insights from our study reduce the risk of infection and add to the bugs. A variant that hopes to help prevent evolution and prevent the emergence of new pathogens. “

Using their research, the team developed insights into the evolution of Mycobacterium tuberculosis, the pathogen that causes tuberculosis, about 5,000 years ago.In the same way as M. AbsesasM. tuberculosis probably began living as an environmental organism, acquiring genes by horizontal gene transfer, which makes certain clones more toxic, and then evolved through multiple rounds of in-host evolution.on the other hand M. Absesas Mycobacterium tuberculosis, which is currently stopped at this point of evolution, has evolved further to allow direct jumps from one person to another.

Dr. Lucy Allen, Head of Research for Cystic Fibrosis Trust, said: The ability to bring together world-leading expertise to address the health priorities identified by people with cystic fibrosis. We look forward to more impressive results in the future from our joint partnership. ”

New treatments kill infections that can be fatal to patients with cystic fibrosis

For more information:
“Stepwise pathogenic evolution of Mycobacterium abscess” Science (2021).… 1126 / science.abb8699

Courtesy of Cambridge University

Quote: Multidrug-resistant infections that are about to evolve within patients with cystic fibrosis (April 29, 2021) are https: // -Obtained from cystic on April 29, 2021. html

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Multidrug-resistant infections that are about to evolve in patients with cystic fibrosis

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