Abstract
The melioidosis bacterium, Burkholderia pseudomallei, is increasingly being recognised as a pathogen in patients with cystic fibrosis (CF). We have recently catalogued genome-wide variation of paired, isogenic B. pseudomallei isolates from seven Australasian CF cases, which were collected between 4 and 55 months apart. Here, we extend this investigation by documenting the transcriptomic changes in B. pseudomallei in five cases. Following growth in an artificial CF sputum medium, four of the five paired isolates exhibited significant differential gene expression (DE) that affected between 32 and 792 genes. The greatest number of DE events was observed between the strains from patient CF9, consistent with the hypermutator status of the latter strain, which is deficient in the DNA mismatch repair protein MutS. Two patient isolates harboured duplications that concomitantly increased expression of the β-lactamase-encoding gene penA, and a 35 kb deletion in another abolished expression of 29 genes. Convergent expression profiles in the chronically-adapted isolates identified two significantly downregulated and 17 significantly upregulated loci, including the resistance-nodulation-division (RND) efflux pump BpeEF–OprC, the quorum-sensing hhqABCDE operon, and a cyanide- and pyocyanin-insensitive cytochrome bd quinol oxidase. These convergent pathoadaptations lead to increased expression of pathways that may suppress competing bacterial and fungal pathogens, and that enhance survival in oxygen-restricted environments, the latter of which may render conventional antibiotics less effective in vivo. Treating chronically adapted B. pseudomallei infections with antibiotics designed to target anaerobic infections, such as the nitroimidazole class of antibiotics, may significantly improve pathogen eradication attempts by exploiting this Achilles heel.
Highlights
The Gram-negative soil-dwelling bacterium Burkholderia pseudomallei causes melioidosis, an opportunistic tropical infectious disease of humans and animals that has a high fatality rate [1]
The elevated number of mutations seen in CF9 is due to a mutS mutation in the latter strain, which confers a hypermutator phenotype, the first time hypermutation has been described in B. pseudomallei [14]; this in turn contributes to a high number of differential gene expression (DE) genes
The melioidosis pathogen, B. pseudomallei, is an uncommon pathogen in cystic fibrosis (CF), with fewer than 30 cases documented worldwide to date. It is an important pathogen in CF airways due to its ability to persist despite treatment and its association with accelerating respiratory decline [13]
Summary
The Gram-negative soil-dwelling bacterium Burkholderia pseudomallei causes melioidosis, an opportunistic tropical infectious disease of humans and animals that has a high fatality rate [1]. B. pseudomallei is found in many tropical and subtropical regions globally, and has been unmasked in temperate and even arid environments following unusually wet weather events [2,3,4]. Infection occurs following percutaneous inoculation from contaminated soil or water, inhalation, or ingestion. Individuals most at risk of contracting melioidosis include diabetics, those with hazardous alcohol consumption and the immunosuppressed. There has been increasing recognition that people with chronic lung diseases such as cystic fibrosis (CF) are at a heightened risk [7, 8]
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