Comparative Metabolic Systems Analysis of Pathogenic Burkholderia

Abstract

Burkholderia cenocepacia and Burkholderia multivorans are opportunistic drug-resistant pathogens that account for the majority of Burkholderia cepacia complex infections in cystic fibrosis patients and also infect other immunocompromised individuals. While they share similar genetic compositions, B. cenocepacia and B. multivorans exhibit important differences in pathogenesis. We have developed reconciled genome-scale metabolic network reconstructions of B. cenocepacia J2315 and B. multivorans ATCC 17616 in parallel (designated iPY1537 and iJB1411, respectively) to compare metabolic abilities and contextualize genetic differences between species. The reconstructions capture the metabolic functions of the two species and give insight into similarities and differences in their virulence and growth capabilities. The two reconstructions have 1,437 reactions in common, and iPY1537 and iJB1411 have 67 and 36 metabolic reactions unique to each, respectively. After curating the extensive reservoir of metabolic genes in Burkholderia, we identified 6 genes essential to growth that are unique to iPY1513 and 13 genes uniquely essential to iJB1411. The reconstructions were refined and validated by comparing in silico growth predictions to in vitro growth capabilities of B. cenocepacia J2315, B. cenocepacia K56-2, and B. multivorans ATCC 17616 on 104 carbon sources. Overall, we identified functional pathways that indicate B. cenocepacia can produce a wider array of virulence factors compared to B. multivorans, which supports the clinical observation that B. cenocepacia is more virulent than B. multivorans. The reconciled reconstructions provide a framework for generating and testing hypotheses on the metabolic and virulence capabilities of these two related emerging pathogens. Multidrug-resistant pathogens are a severe health concern and can cause chronic infections in a variety of patient populations with limited recourse for treatment. Here, we investigate two multidrug-resistant species, Burkholderia cenocepacia and Burkholderia multivorans, of the Burkholderia cepacia complex (BCC) which are considered dangerous and difficult to treat in patients with cystic fibrosis (CF), chronic granulomatous disease, or compromised immune systems (1). With larger genomes (8.06 Mbp and 7.01 Mbp, respectively) than many other multidrug-resistant pathogens, they also contain an expanded reservoir of genes that may assist their ability to avoid clinical eradication (2-4). Because they are nosocomial, transmissible between patients, and also routinely acquired (and reacquired) from the environment, B. cenocepacia and B. multivorans are the two BCC species most commonly isolated from the sputum of CF patients (5-8). In patients with CF, pulmonary infection with BCC can contribute to the rapid deterioration of lung function known as cepacia syndrome, a necrotizing pneumonia that can lead to bacteremia, septicemia, and increased mortality (9, 10). A combination of high antibiotic resistance and decreased immune function in patients makes B. cen...

Burkholderia pseudomallei-derived miR-3473 enhances NF-κB via targeting TRAF3 and is associated with different inflammatory responses compared to Burkholderia thailandensis in murine macrophages

“…Some previous studies have compared Bp and Bt, their intracellular phenotypes and associated host inflammatory response [4, 7, 8, 10, 13]. Wand et al [28] observed an inverse association with their macrophage cytotoxicity and the virulence in mice after Bt infected.…”

“…There are some similarities between Bp and Bt in terms of the ability of intracellular replication, cytokines induction, and immune cell differentiation [7, 8]. Bt has exhibited reduced replication in human macrophages and deficient invasion into epithelial cells compared to Bp [9, 10].…”

1H-NMR-Based Endometabolome Profiles of Burkholderia cenocepacia Clonal Variants Retrieved from a Cystic Fibrosis Patient during Chronic Infection

“…Marked differences in the level of the pyridine nucleotides NADH and NAD + were observed between the first isolate retrieved from the patient and the late isolates IST4129 and IST4134. Since these cofactors are the most important redox carriers involved in metabolism, acting as electron acceptors in catabolic processes and providing the necessary reducing power for energy-producing redox reactions, having been proposed as involved in more than 120 reactions throughout B. cenocepacia metabolism (Fang et al, 2011; Bartell et al, 2014), it is tempting to speculate that the altered redox status of these isolates might contribute to several of the metabolite differences observed. Among the alternative pathways that can be used in the turnover of NAD + to NADH is the biosynthesis of glycine-betaine, L -tyrosine and L -leucine from betaine aldehyde, chorismate and valine, respectively (Bartell et al, 2014).…”

“…The locus name of some of the genes and proteins with altered content in at least one of the late isolates compared with IST439 are also shown. This metabolic scheme was based on information gathered from KEGG PATHWAY Database (http://www.genome.jp/kegg/pathway.html), in BioCyc Database Collection (http://biocyc.org/) and in the metabolic reconstruction of B. cenocepacia J2315 (Bartell et al, 2014). …”

Burkholderia cenocepacia J2315-mediated destruction of Staphylococcus aureus NRS77 biofilms.

“…Rhamnolipids produced by P. aeruginosa have anti-staphylococcal activity [121] and act to decrease biofilm formation in order to maintain water channels [122]. B. cenocepacia J2315 has been shown to possess the operon required for rhamnolipid production [123], although the production of rhamnolipids has not yet been reported in this species. However, the porous biofilm phenotype shown in our study suggests the importance of water channels in B.…”