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.

Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

“…4D, Table S2). Notably, the magnitude of the latter effect is on par with observed differences between hypermutators, such as mutants deficient in the mismatch repair pathway, and their respective parent strains [45][46][47] .…”

Phenotypic traits of Burkholderia spp. associated with ecological adaptation and plant-host interaction

“…The adaptive mechanisms that allow these bacteria to colonize different host are still 442 uncertain, but Nunvar et al (2017) observed that the host immune system can modulate B. 443 cenocepacia evolution during chronic CF infection, since genes that encode proteins involved mutated in sputum isolates of CF-patients.…”

“…could present the plasticity that allow them to occupy different niches. This 524 plasticity strategy can promote increasing fitness, and, once coupled with mutation and 525 selection, can result in a wide range of adaptation across contrasting environmental conditions 526 (Nunvar et al 2017). 527 528…”

The Effect of 2-Thiocyanatopyridine Derivative 11026103 on Burkholderia Cenocepacia: Resistance Mechanisms and Systemic Impact

“…Preparation of sequencing libraries and whole-genome sequencing were performed as described in [3]. Sequencing reads were mapped to the complete reference genome of B. cenocepacia J2315 [28] using Geneious R9 platform [29].…”

“…Patients with cystic fibrosis (CF) are among the ones at the greatest risk of contracting a Bcc infection. Bcc thriving in thick CF sputum are associated with chronic inflammation and significant decline in lung functions; infections with the most virulent Bcc lineages ultimately result in death due to a necrotizing septic pneumonia (cepacia syndrome) [2,3].…”