Certain M. abscessus Variants Linked to Serious CF Lung Infections
Study results may accelerate the development of new, more effective treatments
The clinical outcome of lung infection with Mycobacterium abscessus (M. abscessus) in cystic fibrosis (CF) patients is associated with genetic differences in the bacterium strains, according to a recent study.
The study identified virulence factors related to disease severity, and sheds light on the development of novel and more effective treatments for lung infections caused by M. abscessus.
“This is the first study to define the genetic changes in clinical strains of Mycobacterium abscessus that are responsible for increased virulence and worse health outcomes,” Andres Floto, PhD, director of the UK CF Innovation Hub, said in a Cystic Fibrosis Trust press release.
The study, “Mycobacterium abscessus pathogenesis identified by phenogenomic analyses,” was published in the journal Nature Microbiology.
M. abscessus is a major threat to patients diagnosed with CF as it is responsible for hard-to-treat lung infections, creating a huge burden on their daily life. Treatment may take a long time (several months) and require multiple antibiotics with related side effects. In some cases, the complete elimination of the infection does not occur due to antimicrobial resistance, in which bacteria adapt and stop responding to antibiotics, with consequent inflammation and permanent lung damage.
Therefore, identifying the bacteria strain in each patient can help determine the suitable treatment, and may lead to the development of more effective therapies with fewer side effects.
The UK CF Innovation Hub, a partnership between the UK CF Trust and the University of Cambridge, funded the new study, which builds on previous research.
Researchers investigate 331 strains of M. abscessus
To identify the effect of each genetic variant, the team looked into the genetic profile of 331 strains of M. abscessus. The researchers used different methods to confirm the data, and compared the health outcomes in CF patients infected by the different strains.
At first, a multidimensional analysis characterized M. abscessus variants in five key pathogenic traits: bacterial growth, antibiotic resistance using a selection of therapies recommended by clinical treatment guidelines, infection of a human macrophage cell line (macrophages are a type of white blood cell that play an important role in the immune response), infection in Drosophila melanogaster (aka. fruit fly) model, and clinical outcomes upon infection.
Three groups of M. abscessus were identified according to their characteristics and associated with different clinical outcomes: from ‘rough’ variants, with increased bacterial growth, antimicrobial resistance, and increased mortality in cellular and D. melanogaster models, to ‘smooth’ variants, with the opposite characteristics.
“We discovered three distinct clusters of isolates, each with different virulence traits and associated with a different clinical outcome,” the researchers wrote.
This result highlighted the importance of identifying pathogenic variants based on other characteristics besides antimicrobial susceptibility, and relating that to disease prognosis.
Then, the researchers performed a genome-wide association study, an approach to identify M. abscessus variants associated with different infection severities in patients. They applied a computational model to predict the functional impact of genetic variants, and identified groups of genes implicated in bacterial survival within macrophages and in bacterial secretion systems — required for bacteria to secrete proteins necessary to infect human cells.
One of the genetic variants identified was present in the mycobactin polyketide synthetase (MbtD) gene that encodes a protein involved in the production of mycobactins — which are important for cell processes in bacteria and their survival. This MbtD protein “could be targeted therapeutically,” according to the team.
To relate genetic variants to pathological processes in M. abscessus infections, the researchers used Drosophila, which is a model that depicts some features of human bacterial infection such as immune responses. The team found two genes associated with bacteria virulence and clinical outcomes in CF patients: MAB_0471, a protein related to the bacterial secretion system; and MAB_3317c, an enzyme related to the synthesis of bacterial proteins.
“We found that isolates with either of the two genetic variants were associated with prolonged survival of infected Drosophila and more persistent clinical infection of CF patients,” the researchers wrote.
Overall, this approach “can accurately identify critical gene networks responsible for virulence and other characteristics in poorly understood bacterial pathogens, such as M. abscessus,” the researchers concluded, adding that it can permit “rapid identification of prognostic indicators and potential drug targets.”
About the M. abscessus findings, Floto said “we’ll use this knowledge to develop tests to predict the likely outcome of people infected with M. abscessus, and to create antibiotics against several of these newly discovered virulence factors.”
Lucy Allen, PhD, director of research at the CF Trust, added: “We are delighted that researchers within the UK CF Innovation Hub are being so successful in understanding more about how M. abscessus causes such serious infections in people with CF. We’re excited about how these results might be used to accelerate the development of new, more effective treatments.”
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