The TonB3 System in the Human Pathogen Vibrio vulnificus Is under the Control of the Global Regulators Lrp and Cyclic AMP Receptor Protein

Alice, Alejandro F.; Crosa, Jorge H.

doi:10.1128/jb.06614-11

Cited by 14 publications

(17 citation statements)

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“…The promoters of tonB3 ( VV0250-VV0244 ) and cadBA ( VV2382-VV2383 ) have been previously demonstrated to be bound by Lrp [ 32 , 33 ]. In these two promoters and the 8 Lrp-binding promoters we identified in this study, a 14-bp consensus DNA sequence, mkCrTTkwAyTsTG (m: A or C; k: G or T; r: A or G; w: A or T; y: C or T; s: G or C), was found.…”

Section: Resultsmentioning

confidence: 99%

“…This regulator has been shown to be involved in survival under stresses, like low pH, low temperature and high salt [ 55 ]. It is also involved in the regulation of cadBA, which is associated with acid tolerance [ 33 ], and the TonB3 system of unknown function [ 32 ] by direct binding to their promoters. But, not until now that Lrp is demonstrated to be also an important virulence regulator in this study.…”

Section: Discussionmentioning

confidence: 99%

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Lrp, a global regulator, regulates the virulence of Vibrio vulnificus

Hung

Weng

et al. 2017

J Biomed Sci

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BackgroundAn attenuated mutant (designated NY303) of Vibrio vulnificus, which causes serious wound infection and septicemia in humans, was isolated fortuitously from a clinical strain YJ016. This mutant was defective in cytotoxicity, migration on soft agar and virulence in the mouse. The purpose of this study was to map the mutation in this attenuated mutant and further explore how the gene thus identified is involved in virulence.MethodsThe whole genome sequence of mutant NY303 determined by next-generation sequencing was compared with that of strain YJ016 to map the mutations. By isolating and characterizing the specific gene-knockout mutants, the gene associated with the phenotype of mutant NY303 was identified. This gene encodes a global regulator, Lrp. A mutant, YH01, deficient in Lrp was isolated and examined in vitro, in vivo and ex vivo to find the affected virulence mechanisms. The target genes of Lrp were further identified by comparing the transcriptomes, which were determined by RNA-seq, of strain YJ016 and mutant YH01. The promoters bound by Lrp were identified by genome footprinting-sequencing, and those related with virulence were further examined by electrophoretic mobility shift assay.ResultsA mutation in lrp was shown to be associated with the reduced cytotoxicity, chemotaxis and virulence of mutant NY303. Mutant YH01 exhibited a phenotype resembling that of mutant NY303, and was defective in colonization in the mouse and growth in mouse serum, but not the antiphagocytosis ability. 596 and 95 genes were down- and up-regulated, respectively, in mutant YH01. Many of the genes involved in secretion of the MARTX cytotoxin, chemotaxis and iron-acquisition were down-regulated in mutant YH01. The lrp gene, which was shown to be negatively autoregulated, and 7 down-regulated virulence-associated genes were bound by Lrp in their promoters. A 14-bp consensus sequence, mkCrTTkwAyTsTG, putatively recognized by Lrp was identified in the promoters of these genes.ConclusionsLrp is a global regulator involved in regulation of cytotoxicity, chemotaxis and iron-acquisition in V. vulnificus. Down-regulation of many of the genes associated with these properties may be responsible, at least partly, for loss of virulence in mutant NY303.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-017-0361-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lrp, a global regulator, regulates the virulence of Vibrio vulnificus

Hung

Weng

et al. 2017

J Biomed Sci

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“…The maintenance of a third TonB system in V. vulnificus CMCP6 genomes, which is similar to the TonB2 system in its gene arrangement and orientation (20)(21)(22), raised the following questions. Why has V. vulnificus CMCP6 maintained three TonB systems throughout evolution?…”

Section: Discussionmentioning

confidence: 99%

“…As a result of the pivotal findings of Crosa's group, the importance of TonB1 and TonB2 systems in the iron transport of siderophores and in the pathogenesis of V. vulnificus has been highlighted (20,21). Also, they reported that the functionally elusive TonB3 has a unique regulation mechanism consisting of Lrp (L-leucine responsive protein) and CRP (cAMP receptor protein) (20,22). Based upon the regulation of TonB3 system by Lrp and CRP, they proposed that TonB3 would function to integrate different environmental signals such as glucose starvation and the transition between "feast" and "famine."…”

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confidence: 99%

All Three TonB Systems Are Required for Vibrio vulnificus CMCP6 Tissue Invasiveness by Controlling Flagellum Expression

et al. 2016

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e TonB systems actively transport iron-bound substrates across the outer membranes of Gram-negative bacteria. Vibrio vulnificus CMCP6, which causes fatal septicemia and necrotizing wound infections, possesses three active TonB systems. It is not known why V. vulnificus CMCP6 has maintained three TonB systems throughout its evolution. The TonB1 and TonB2 systems are relatively well characterized, while the pathophysiological function of the TonB3 system is still elusive. A reverse transcription-PCR (RT-PCR) study showed that the tonB1 and tonB2 genes are preferentially induced in vivo, whereas tonB3 is persistently transcribed, albeit at low expression levels, under both in vitro and in vivo conditions. The goal of the present study was to elucidate the raison d'être of these three TonB systems. In contrast to previous studies, we constructed in-frame single-, double-, and triple-deletion mutants of the entire structural genes in TonB loci, and the changes in various virulence-related phenotypes were evaluated. Surprisingly, only the tonB123 mutant exhibited a significant delay in killing eukaryotic cells, which was complemented in trans with any TonB operon. Very interestingly, we discovered that flagellum biogenesis was defective in the tonB123 mutant. The loss of flagellation contributed to severe defects in motility and adhesion of the mutant. Because of the difficulty of making contact with host cells, the mutant manifested defective RtxA1 toxin production, which resulted in impaired invasiveness, delayed cytotoxicity, and decreased lethality for mice. Taken together, these results indicate that a series of virulence defects in all three TonB systems of V. vulnificus CMCP6 coordinately complement each other for iron assimilation and full virulence expression by ensuring flagellar biogenesis. Vibrio vulnificus is a halophilic estuarine pathogen that causes fatal septicemia and necrotizing wound infections in patients suffering from hepatic diseases with high levels of circulating iron or who are immunocompromised (1-5). Infection with V. vulnificus typically shows rapid progression and mortality rates greater than 50% (6, 7). In Gram-negative bacteria, the inner membrane protein complex TonB plays a crucial role in the uptake of iron (8, 9), which is an important micronutrient for numerous biological processes (10-12). TonB complexes transduce the proton motive force (PMF) of the cytoplasmic membrane to energize iron-siderophore complex transport through a specific TonB-dependent transporter (TBDT) across the outer membrane (OM) (9,13,14). This system's known biological roles had been restricted to iron complexes (15, 16) and vitamin B 12 (14), but recent experimental evidence of the TonB-energized transport of nickel and various carbohydrates suggests that the number and variety of TonB-dependent substrates have been underestimated (17)(18)(19). Unlike the single TonB system in Escherichia coli (8), the genomes of Vibrio species carry multiple TonB systems. Interestingly, three TonB systems were first report...

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“…Crp binds upstream of the V. vulnificus hupA gene and activates its expression (241). Crp also induces the expression of tonB3 (137) and the aerobactin receptor gene iutA (243) in V. vulnificus. Crp and cAMP may couple growth on carbon sources other than glucose with the increased need for iron required for full metabolism of these substrates.…”

Section: Other Environmental Sensors and Regulators For Iron Acquisitionmentioning

confidence: 99%

Vibrio Iron Transport: Evolutionary Adaptation to Life in Multiple Environments

Payne

Mey

Wyckoff

2016

Microbiol Mol Biol Rev

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SUMMARYIron is an essential element forVibriospp., but the acquisition of iron is complicated by its tendency to form insoluble ferric complexes in nature and its association with high-affinity iron-binding proteins in the host. Vibrios occupy a variety of different niches, and each of these niches presents particular challenges for acquiring sufficient iron.Vibriospecies have evolved a wide array of iron transport systems that allow the bacteria to compete for this essential element in each of its habitats. These systems include the secretion and uptake of high-affinity iron-binding compounds (siderophores) as well as transport systems for iron bound to host complexes. Transporters for ferric and ferrous iron not complexed to siderophores are also common toVibriospecies. Some of the genes encoding these systems show evidence of horizontal transmission, and the ability to acquire and incorporate additional iron transport systems may have allowedVibriospecies to more rapidly adapt to new environmental niches. While too little iron prevents growth of the bacteria, too much can be lethal. The appropriate balance is maintained in vibrios through complex regulatory networks involving transcriptional repressors and activators and small RNAs (sRNAs) that act posttranscriptionally. Examination of the number and variety of iron transport systems found inVibriospp. offers insights into how this group of bacteria has adapted to such a wide range of habitats.

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The TonB3 System in the Human Pathogen Vibrio vulnificus Is under the Control of the Global Regulators Lrp and Cyclic AMP Receptor Protein

Cited by 14 publications

References 71 publications

Lrp, a global regulator, regulates the virulence of Vibrio vulnificus

Lrp, a global regulator, regulates the virulence of Vibrio vulnificus

All Three TonB Systems Are Required for Vibrio vulnificus CMCP6 Tissue Invasiveness by Controlling Flagellum Expression

Vibrio Iron Transport: Evolutionary Adaptation to Life in Multiple Environments

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