title: Within-Host Evolution ofBurkholderia pseudomalleiduring Chronic Infection of Seven Australasian Cystic Fibrosis Patients.
abstract: Cystic fibrosis (CF) is a genetic disorder characterized by progressive lung function decline. CF patients are at an increased risk of respiratory infections, including those by the environmental bacteriumBurkholderia pseudomallei, the causative agent of melioidosis. Here, we compared the genomes ofB. pseudomalleiisolates collected between ~4 and 55 months apart from seven chronically infected CF patients. Overall, theB. pseudomalleistrains showed evolutionary patterns similar to those of other chronic infections, including emergence of antibiotic resistance, genome reduction, and deleterious mutations in genes involved in virulence, metabolism, environmental survival, and cell wall components. We documented the first reportedB. pseudomalleihypermutators, which were likely caused by defective MutS. Further, our study identified both known and novel molecular mechanisms conferring resistance to three of the five clinically important antibiotics for melioidosis treatment. Our report highlights the exquisite adaptability of microorganisms to long-term persistence in their environment and the ongoing challenges of antibiotic treatment in eradicating pathogens in the CF lung. Convergent evolution with other CF pathogens hints at a degree of predictability in bacterial evolution in the CF lung and potential targeted eradication of chronic CF infections in the future.IMPORTANCEBurkholderia pseudomallei, the causative agent of melioidosis, is an environmental opportunistic bacterium that typically infects immunocompromised people and those with certain risk factors such as cystic fibrosis (CF). Patients with CF tend to develop chronic melioidosis infections, for reasons that are not well understood. This report is the first to describeB. pseudomalleievolution within the CF lung during chronic infection. We show that the pathways by whichB. pseudomalleiadapts to the CF lung are similar to those seen in better-studied CF pathogens such asPseudomonas aeruginosa,Staphylococcus aureus, andBurkholderia cepaciacomplex species. Adaptations include the accumulation of antibiotic resistance, loss of nonessential genes, metabolic alterations, and virulence factor attenuation. Known and novel mechanisms of resistance to three of the five antibiotics used in melioidosis treatment were identified. Similar pathways of evolution in CF pathogens, includingB. pseudomallei, provide exciting avenues for more-targeted treatment of chronic, recalcitrant infections.
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
authors.forename: Linda T
authors.identifier: 0000-0002-4174-1142
authors.initials: LT
authors.lastname: Viberg
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.|Centre for Animal Health Innovation, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia.
authors.forename: Derek S
authors.identifier: 0000-0002-6944-3980
authors.initials: DS
authors.lastname: Sarovich
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.|Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland.|Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kidd
authors.affiliation: Department of Respiratory Medicine, The Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia.
authors.forename: James B
authors.initials: JB
authors.lastname: Geake
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Department of Thoracic Medicine, The Prince Charles Hospital, Chermside, Queensland, Australia.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bell
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.|Department of Infectious Diseases and Northern Territory Medical Program, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Currie
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia eprice@usc.edu.au.|Centre for Animal Health Innovation, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia.
authors.forename: Erin P
authors.identifier: 0000-0002-1079-4882
authors.initials: EP
authors.lastname: Price
mesh_terms: D000220:Adaptation, Biological; D001315:Australia; D016957:Burkholderia pseudomallei / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications*; D019143:Evolution, Molecular; D016680:Genome, Bacterial; D006801:Humans; D008554:Melioidosis / Q000382:microbiology* / Q000473:pathology; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
keywords: Burkholderia pseudomallei; antibiotic resistance; cystic fibrosis; melioidosis; parallelism; reductive evolution; whole-genome sequencing; within-host evolution