Scientists have been able to track how a multi-drug resistant organism can evolve and spread widely among cystic fibrosis patients – showing that it can evolve rapidly in an individual during chronic infection. The researchers say their findings underscore the need to treat patients with Mycobacterium abscessus immediate infection, contrary to current medical practice.
In the UK, around one in 2,500 children are born with cystic fibrosis, an inherited disease that clogs the lungs with thick, sticky mucus. The condition tends to reduce the life expectancy of the patients.
During the last years, M. abscessus, a species of bacteria resistant to several drugs, has become a significant global threat to people with cystic fibrosis and other lung diseases. It can cause severe pneumonia leading to accelerated inflammatory damage to the lungs and may prevent safe lung transplantation. It is also extremely difficult to treat – less 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 1173 M. abscessus samples taken from 526 patients to study how the body evolved – and continues to evolve. The samples were collected from cystic fibrosis clinics in the UK, as well as centers in Europe, the US and Australia.
The team discovered two key processes that play an important role in the evolution of the organism. The first is known as horizontal gene transfer – a process by which bacteria pick up genes or sections of DNA from other bacteria found in the environment. Unlike classical evolution, which is a slow and gradual process, horizontal gene transfer can lead to big leaps in the pathogen’s evolution, potentially allowing it to suddenly become much more virulent.
The second process is evolution within the host. Due to the shape of the lung, several versions of the bacteria can evolve in parallel – and the longer the infection lasts, the more opportunities they have to evolve, with the fittest variants eventually winning out. Similar phenomena have been observed in the development of new variants of SARS-CoV-2 in immunocompromised patients.
Professor Andres Floto, co-lead author of the Center for AI in Medicine (CCAIM) and the Department of Medicine at the University of Cambridge and the Cambridge Center for Lung Infection at Royal Papworth Hospital, said: “What you get, it is a parallel evolution in different parts of an individual’s lung. This gives bacteria the ability to roll multiple dice until they find the most successful mutations. The net result is a very efficient way to generate adaptations to the host and increase virulence.
“This suggests that you might need to treat the infection as soon as it’s identified. For now, because the drugs can cause unpleasant side effects and need to be given over a long period – often up to 18 months – – Doctors usually wait to see if the bacteria is causing the disease before treating the infection, but what this does is give the bug enough time to grow repeatedly, which makes treatment more difficult.
Professor Floto and his colleagues have already advocated routine monitoring of patients with cystic fibrosis 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 monitoring is carried out regularly in many centers in the UK.
Using mathematical models, the team was able to retrace the evolution of the organism in a single individual and recreate its trajectory, looking for key mutations in every organism in every part of the lung. By comparing samples from several patients, they were then able to identify the key set of genes that allowed this organism to transform into a potentially fatal pathogen.
These adaptations can happen very quickly, but the team found that their ability to transmit between patients was limited: ironically, the mutations that allowed the body to become a more effective pathogen in the patient also reduced its ability. to survive on external surfaces and in the air – the key mechanisms by which it is thought to be transmitted between people.
One of the most important genetic changes the team observed probably contributed to M. abscessus become resistant to nitric oxide, a compound naturally produced by the human immune system. The team will soon begin a clinical trial to stimulate nitric oxide in patients’ lungs using inhaled acidified nitrite, which they hope will become a new treatment for the devastating infection.
Examining DNA taken from patient samples is also important to help understand routes of transmission. These techniques are commonly used in Cambridge hospitals to map the spread of infections such as MRSA and C. difficile – and more recently, SARS-CoV-2. An overview of the spread of M. abscessus helped design the new Royal Papworth Hospital building, opened in 2019, which features a state-of-the-art ventilation system to prevent transmission. The team recently published a study showing that this ventilation system was very effective in reducing the amount of bacteria in the air.
Professor Julian Parkhill, co-lead author of the Department of Veterinary Medicine at the University of Cambridge, added: “M. abscessus can be a very difficult infection to treat and can be very dangerous for people with cystic fibrosis, but we hope the information from our research will help us reduce the risk of transmission, stop the bug from progressing and potentially prevent the emergence of new pathogens. variants. “
The team used their research to develop information about the development of M. tuberculosis – the pathogen that causes tuberculosis about 5,000 years ago. The same way as M. abscessus, M. tuberculosis probably began life as an environmental organism, acquired genes by horizontal transfer that made some clones more virulent, and then evolved through multiple cycles of intra-host evolution. While M. abscessus is currently stopped at this developmental stage, M. tuberculosis has evolved further so that it can pass directly from one person to another.
Dr Lucy Allen, Director of Research at the Cystic Fibrosis Trust, said: “This exciting research brings real hope to find better ways to treat lung infections resistant to other drugs. Our innovation center co-funded with the University of Cambridge really shows the power of bringing together leading global expertise to tackle a health priority identified by people with cystic fibrosis. We expect to see more impressive results in the future through our joint partnership. “
The study was funded by the Wellcome Trust, the Cystic Fibrosis Trust, the NIHR Cambridge Biomedical Research Center, and the Botnar Foundation