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Pulse - Summer 2017 Genomics Reveal How Bacteria Evolve in Cystic Fibrosis Patients

Drexel scientists have made new headway in under standing how a deadly pathogen evolves during chronic lung infections in cystic fibrosis patients.

Cystic fibrosis is the most common fatal genetic disorder in the world. It is caused by a gene mutation that leads to a buildup of mucus in the lungs, creating an optimal environment for bacteria to thrive.

Colony morphologies of 96 Burkholderia cenocepacia isolates from cystic fibrosis patients (University of British Columbia).

Colony morphologies of 96 Burkholderia cenocepacia isolates from cystic fibrosis patients (University of British Columbia).

Among these pathogens is Burkholderia cenocepacia — one of the most common and life-threatening species found in CF patients that is also easily transmitted and often resistant to antibiotics. This bacterium is also protected by a sticky biofilm formed by groups of the organism, which strengthens its resistance to antibiotics. Until now, researchers had only a poor understanding of how B. cenocepacia adapts to the CF lung to sustain long-term chronic infections.

But Drexel University College of Medicine and University of British Columbia scientists have now shown how long-term infection leads to genetic and physical changes in this species. Their study, published in Genome Research* in March, provides the first comprehensive genome- phenome analyses of B. cenocepacia infection in cystic fibrosis lungs.

"By looking at changes in the genome over time, we were able to see patterns — common themes that help us to better understand how this particular species evolves in its environment and how CF patients become chronically infected," says study co-corresponding author Joshua Chang Mell, PhD, an assistant professor in the Department of Microbiology & Immunology at the College of Medicine.

The researchers collected 215 bacterial samples isolated from 16 cystic fibrosis patients over a period of time, spanning up to 20 years for each patient. After using whole genome sequencing, they found that long-term infection leads to significant genetic changes, as well as physical changes, such as progressive declines in bacterial motility, and changes in biofilm formation over time. The researchers also observed broad phenotypic and genotypic variation for samples obtained from the same patient at the same time.

The study increases the number of genome sequences for the species by more than 10-fold, and by coupling these genomes with extensive phenotypic tests, it offers a unique resource for understanding how the species evolves in the context of chronic lung infection.

Based on anecdotal observations and single strain reports, the researchers expected that the genome of B. cenocepacia was flexible, but had no idea of the scope and scale of how promiscuous the gene content and genome architecture would be in a modest-sized patient cohort.

What they found most surprising was that some bacterial traits typically associated with pathogenesis (namely motility and biofilm formation) actually became less pronounced over time.

"This suggests that one way the bacterium may be adapting to long-term chronic lung infection is by becoming less aggressive and thus potentially more able to avoid the immune system," says Mell.

The researchers also identified numerous genes associated with swimming motility and biofilm formation. Future work will show whether these might be promising targets for future drugs.

"We expect this rich resource will provide for interrogating clinical isolates of B. cenocepacia both to address basic biological questions about how bacteria evolve within infections and to help characterize future outbreaks," the authors conclude.

* Joshua Chang Mell, PhD, assistant professor; Rachel L. Ehrlich, MS, bioinformatics programmer; Sergey Balashov, PhD, genomics core facility manager; Garth D. Ehrlich, PhD, professor, all in the Department of Microbiology & Immunology; and colleagues published "Phenotypic Diversity and Genotypic Flexibility of Burkholderia cenocepacia During Long-Term Chronic Infection of Cystic Fibrosis Lungs" (PMCID: PMC5378182) in the April 2017 issue of Genome Research (published online March 21).

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