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Mycobacterium Evolution Study Suggests Early Cystic Fibrosis Infection Treatment

NEW YORK – Non-tuberculous mycobacteria (NTM) that take up residence in the lungs of cystic fibrosis (CF) patients appear capable of evolving quickly during chronic infections, according to a genomic study of Mycobacterium abscessus isolates in infected individuals and the environment. The results hint at the importance of treating such infections promptly.

Findings from the study, published in Science on Thursday, suggest that early eradication of NTM infections may be the best strategy for individuals with cystic fibrosis, co-senior and co-corresponding author Andres Floto, a researcher affiliated with the University of Cambridge and Royal Papworth Hospital, explained in an email.

In contrast, the current standard of care — based on guidelines established by the American Thoracic Society and the Infectious Diseases Society of America more than a decade ago — is to treat cystic fibrosis patients for the severe pneumonia- and lung inflammation-related bug only after they have had multiple NTM-positive cultures and developed pulmonary disease features that can be detected with radiological methods.

"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," Floto explained in a statement. "But what this does is give the bug plenty of time to evolve repeatedly, potentially making it more difficult to treat."

For their analysis, investigators at the University of Cambridge, the Wellcome Sanger Institute, and elsewhere used whole-genome sequencing, pan-genome analyses, transcriptome and methylome clues, computational modeling, and other approaches to try to untangle M. abscessus evolution, which has already produced a handful of multi-drug-resistant dominant circulating clones found around the world.

Based on sequences for nearly 1,200 M. abscessus clinical isolates collected from 526 individuals treated at CF clinics in the UK, Europe, North America, or Australia — along with genetic insights from M. abscessus subclonal populations tracked over time by deep sequencing in samples from 18 individuals with chronic infections — they retraced characteristic steps in M. abscessus evolution in different environments.

In particular, the results pointed to horizontal gene transfer events involving DNA methyltransferase enzymes and other epigenetic regulators in response to selection events in M. abscessus microbes found in the environment, followed by relatively rapid adaptations within the lungs of chronically infected cystic fibrosis patients, including the advent of clones with recurrent mutations linked to more virulent M. abscessus isolates that are better able to dodge host macrophage immune cells.

"What you end up with is parallel evolution in different parts of an individual's lung," Floto explained in a statement. "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."

By bringing in findings from a 2016 study by members of the same team, the researchers suggested that M. abscessus transmission from one person to another likely occurs through so-called fomites, or microbe-contaminated surfaces, leading to more constrained evolution as M. abscessus mutations developed in response to immune cells in CF patient lungs face a distinct environment.

"Ultimately, we predict that opportunities for direct transmission of emergent mycobacteria (potentially through increases in population density and/or host susceptibility) will permit unconstrained, accelerated evolution into an obligate human pathogen (as occurred in M. tuberculosis several thousand years ago)," the authors wrote.

Even so, the risk of more extensive pathogen evolution and transmission is expected to decline if more infections are treated early, multiple samples are assessed from those who are infected, and enhanced infection control measures are adopted to reduce M. abscessus transmission between CF patients, the authors suggested.

"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," co-senior and co-corresponding author Julian Parkhill, a researcher at the University of Cambridge, said in a statement.

In a related commentary in Science, Rossa Brugha and Helen Spencer, researchers at the Great Ormand Street Hospital and UCL Great Ormand Street Institute of Child Health, discussed the study's findings within the broader context of M. abscessus management in cystic fibrosis, calling the new results "a timely reminder that individuals with CF remain at risk of infection with highly resistant organisms, and that vigilance regarding infection control measures must remain a key focus in CF care."

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