Characterization of the Burkholderia cenocepacia TonB Mutant as a Potential Live Attenuated Vaccine

Pradenas, Gonzalo A.; Myers, Julia N.; Torres, Alfredo G.

doi:10.3390/vaccines5040033

Cited by 13 publications

(19 citation statements)

References 37 publications

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“…However, further study of the essential genomes of other species of the genus Burkholderia is needed to confirm this hypothesis. Efforts are ongoing to find alternatives to conventional treatments for pathogenic species of the genus Burkholderia [ 103–106 ]. The envelope proteins identified in this work may represent ideal candidates for immunogenic targeting, as conserved essential proteins are less prone to variability.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the Burkholderia cenocepacia K56-2 essential genome reveals cell envelope functions that are uniquely required for survival in species of the genus Burkholderia

et al. 2017

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Burkholderia cenocepacia K56-2 belongs to the Burkholderia cepacia complex, a group of Gram-negative opportunistic pathogens that have large and dynamic genomes. In this work, we identified the essential genome of B. cenocepacia K56-2 using high-density transposon mutagenesis and insertion site sequencing (Tn-seq circle). We constructed a library of one million transposon mutants and identified the transposon insertions at an average of one insertion per 27 bp. The probability of gene essentiality was determined by comparing of the insertion density per gene with the variance of neutral datasets generated by Monte Carlo simulations. Five hundred and eight genes were not significantly disrupted, suggesting that these genes are essential for survival in rich, undefined medium. Comparison of the B. cenocepacia K56-2 essential genome with that of the closely related B. cenocepacia J2315 revealed partial overlapping, suggesting that some essential genes are strain-specific. Furthermore, 158 essential genes were conserved in B. cenocepacia and two species belonging to the Burkholderia pseudomallei complex, B. pseudomallei K96243 and Burkholderia thailandensis E264. Porins, including OpcC, a lysophospholipid transporter, LplT, and a protein involved in the modification of lipid A with aminoarabinose were found to be essential in Burkholderia genomes but not in other bacterial essential genomes identified so far. Our results highlight the existence of cell envelope processes that are uniquely essential in species of the genus Burkholderia for which the essential genomes have been identified by Tn-seq.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of the Burkholderia cenocepacia K56-2 essential genome reveals cell envelope functions that are uniquely required for survival in species of the genus Burkholderia

et al. 2017

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“…As to TonB3 druggability, it is important to underline that tonB3 is among the genes whose expression is upregulated during bacteremia (56) and that no homologs of TonB3 have so far been identified in mammals, hopefully limiting toxicity issues related to the administration of TonB3 inhibitors. Moreover, some studies indicate that avirulent tonB mutants represent suitable backbone strains for future vaccine development against Klebsiella pneumoniae, Burkholderia mallei, and Burkholderia cenocepacia infections (51,57,58). Given the increasing antibiotic resistances of A. baumannii and the essentiality of iron for A. baumannii growth in vivo, the data presented in this study highlight TonB3 as a suitable target for the development of new antimicrobial compounds and pave the way to testing tonB3 mutants as attenuated A. baumannii vaccines.…”

Section: Discussionmentioning

confidence: 82%

Contribution of Active Iron Uptake to Acinetobacter baumannii Pathogenicity

et al. 2019

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Acinetobacter baumannii is an important nosocomial pathogen. Mechanisms that allow A. baumannii to cause human infection are still poorly understood. Iron is an essential nutrient for bacterial growth in vivo, and the multiplicity of iron uptake systems in A. baumannii suggests that iron acquisition contributes to the ability of A. baumannii to cause infection. In Gram-negative bacteria, active transport of ferrisiderophores and heme relies on the conserved TonB-ExbB-ExbD energytransducing complex, while active uptake of ferrous iron is mediated by the Feo system. The A. baumannii genome invariably contains three tonB genes (tonB1, tonB2, and tonB3), whose role in iron uptake is poorly understood. Here, we generated A. baumannii mutants with knockout mutations in the feo and/or tonB gene. We report that tonB3 is essential for A. baumannii growth under iron-limiting conditions, whereas tonB1, tonB2, and feoB appear to be dispensable for ferric iron uptake. tonB3 deletion resulted in reduced intracellular iron content despite siderophore overproduction, supporting a key role of TonB3 in iron uptake. In contrast to the case for tonB1 and tonB2, the promoters of tonB3 and feo contain functional Fur boxes and are upregulated in iron-poor media. Both TonB3 and Feo systems are required for growth in complement-free human serum and contribute to resistance to the bactericidal activity of normal human serum, but only TonB3 appears to be essential for virulence in insect and mouse models of infection. Our findings highlight a central role of the TonB3 system for A. baumannii pathogenicity. Hence, TonB3 represents a promising target for novel antibacterial therapies and for the generation of attenuated vaccine strains.

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“…The uptake of ferric siderophore complexes by Burkholderia species require different outer membrane receptors that interact with an inner membrane TonB complex (TonB, ExbB, and ExbD) (17, 18). Previously, our group demonstrated that disruption of tonB reduces the virulence of Burkholderia mallei and Burkholderia cenocepacia both in vitro and in vivo (19, 20).…”

Section: Introductionmentioning

confidence: 99%

Burkholderia pseudomallei Δ tonB Δ hcp1 Live Attenuated Vaccine Strain Elicits Full Protective Immunity against Aerosolized Melioidosis Infection

Khakhum

Bharaj

Myers

et al. 2019

mSphere

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In recent years, an increasing number of melioidosis cases have been reported in several regions where melioidosis is endemic and in areas where melioidosis had not commonly been diagnosed. Currently, the estimated burden of disease is around 165,000 new cases annually, including 89,000 cases that have fatal outcomes. This life-threatening infectious disease is caused by B. pseudomallei, which is classified as a Tier 1 select agent. Due to the high case fatality rate, intrinsic resistance to multiple antibiotic treatments, susceptibility to infection via the aerosol route, and potential use as a bioweapon, we have developed an effective live attenuated PBK001 vaccine capable of protecting against aerosolized melioidosis.

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Characterization of the Burkholderia cenocepacia TonB Mutant as a Potential Live Attenuated Vaccine

Cited by 13 publications

References 37 publications

Comparative analysis of the Burkholderia cenocepacia K56-2 essential genome reveals cell envelope functions that are uniquely required for survival in species of the genus Burkholderia

Comparative analysis of the Burkholderia cenocepacia K56-2 essential genome reveals cell envelope functions that are uniquely required for survival in species of the genus Burkholderia

Contribution of Active Iron Uptake to Acinetobacter baumannii Pathogenicity

Burkholderia pseudomallei Δ tonB Δ hcp1 Live Attenuated Vaccine Strain Elicits Full Protective Immunity against Aerosolized Melioidosis Infection

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