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What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics.

ABSTRACT: Burkholderia cenocepacia causes severe pulmonary infections in cystic fibrosis (CF) patients. Since the bacterium is virtually untreatable by antibiotics, chronic infections persist for years and might develop into fatal septic pneumonia (cepacia syndrome, CS). To devise new strategies to combat chronic B. cenocepacia infections, it is essential to obtain comprehensive knowledge about their pathogenesis. We conducted a comparative genomic analysis of 32 Czech isolates of epidemic clone B. cenocepacia ST32 isolated from various stages of chronic infection in 8 CF patients. High numbers of large-scale deletions were found to occur during chronic infection, affecting preferentially genomic islands and nonessential replicons. Recombination between insertion sequences (IS) was inferred as the mechanism behind deletion formation; the most numerous IS group was specific for the ST32 clone and has undergone transposition burst since its divergence. Genes functionally related to transition metal metabolism were identified as hotspots for deletions and IS insertions. This functional category was also represented among genes where nonsynonymous point mutations and indels occurred parallelly among patients. Another category exhibiting parallel mutations was oxidative stress protection; mutations in catalase KatG resulted in impaired detoxification of hydrogen peroxide. Deep sequencing revealed substantial polymorphism in genes of both categories within the sputum B. cenocepacia ST32 populations, indicating extensive adaptive evolution. Neither oxidative stress response nor transition metal metabolism genes were previously reported to undergo parallel evolution during chronic CF infection. Mutations in katG and copper metabolism genes were overrepresented in patients where chronic infection developed into CS. Among professional phagocytes, macrophages use both hydrogen peroxide and copper for their bactericidal activity; our results thus tentatively point to macrophages as suspects in pathogenesis towards the fatal CS.

SUBMITTER: Nunvar J

PROVIDER: S-EPMC5739508 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics.

Nunvar Jaroslav J Capek Vaclav V Fiser Karel K Fila Libor L Drevinek Pavel P

PLoS pathogens 20171211 12

Burkholderia cenocepacia causes severe pulmonary infections in cystic fibrosis (CF) patients. Since the bacterium is virtually untreatable by antibiotics, chronic infections persist for years and might develop into fatal septic pneumonia (cepacia syndrome, CS). To devise new strategies to combat chronic B. cenocepacia infections, it is essential to obtain comprehensive knowledge about their pathogenesis. We conducted a comparative genomic analysis of 32 Czech isolates of epidemic clone B. cenoce ...[more]

PMID: 29228063

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Project description:During cystic fibrosis (CF) chronic lung infections, bacteria of the Burkholderia cepacia complex (Bcc) are exposed for several years to a stressful and changing environment. These environmental challenges results in genetic changes of the initial infecting strain with the consequent diversification of genotypes and phenotypes. The exploitation of functional and comparative genomic approaches has suggested that such diversification is associated with massive metabolic remodeling but these alterations are poorly understood. In the present work, we have explored a high resolution 1H-NMR-based metabolomic approach coupled to multivariate analysis to compare the endometabolome of three B. cenocepacia clonal variants retrieved from a CF patient from the onset of infection (IST439) until death with cepacia syndrome after 3.5 years (IST4113 and IST4134), to complement former proteomic and transcriptomic analyses. A fourth clonal variant (IST4129) retrieved from the same CF patient when the clinical condition worsened during the last months of life, was also examined since it was found to lack the third replicon. The metabolomic profiles obtained, based on the complete 1H-NMR spectra, highlight the separation of the four clonal variants examined, the most distinct profile corresponding to IST4129. Results indicate a variable content of several amino acids in the different isolates examined and suggest that glycolysis and the glyoxylate shunt are favored in late variants. Moreover, the concentration of two metabolites with demonstrated cellular protective functions against stress, glycine-betaine and trehalose, is different in the different isolates examined. However, no clear correlation could be established between their content and stress tolerance. For example, IST4113, previously found to be the most resistant variant to antimicrobials of different classes, exhibits low levels of trehalose and glycine-betaine but the highest resistance to heat and oxidative stress. Also, IST4129, with a high level of glycine-betaine but lacking the third replicon, previously associated with stress resistance and virulence, exhibits the highest susceptibility to all the stresses tested. Taken together, results from this study provide insights into the metabolic diversification of B. cenocepacia clonal variants during long-term infection of the CF airways.

Project description:Cystic fibrosis (CF) is the most common inherited lethal disease of Caucasians which results in multi organ dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B. cepacia) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation and is resistant to nearly all available antibiotics. In CFTR ?F508 mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1?. It is believed that intracellular bacterial survival contributes to the persistence of the bacterium. Here we show for the first time that in wild-type macrophages but not in ?F508 macrophages, many B. cepacia reside in autophagosomes that fuse with lysosomes at later stages of infection. Accordingly, association and intracellular survival of B. cepacia are higher in CFTR-?F508 (?F508) macrophages than in WT macrophages. An autophagosome is a compartment that engulfs non-functional organelles and parts of the cytoplasm then delivers them to the lysosome for degradation to produce nutrients during periods of starvation or stress. Furthermore, we show that B. cepacia downregulates autophagy genes in WT and ?F508 macrophages. However, autophagy dysfunction is more pronounced in ?F508 macrophages since they already have compromised autophagy activity. We demonstrate that the autophagy-stimulating agent, rapamycin markedly decreases B. cepacia infection in vitro by enhancing the clearance of B. cepacia via induced autophagy. In vivo, Rapamycin decreases bacterial burden in the lungs of CF mice and drastically reduces signs of lung inflammation. Together, our studies reveal that if efficiently activated, autophagy can control B. cepacia infection and ameliorate the associated inflammation. Therefore, autophagy is a novel target for new drug development for CF patients to control B. cepacia infection and accompanying inflammation.

Dataset Information

What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics.

Publications

What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics.

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