RTX Toxin Enhances the Survival of Vibrio vulnificus During Infection by Protecting the Organism From Phagocytosis

Lo, Horng‐Ren; Lin, Jen-Hsing; Chen, Yi‐Hsuan; Chun-Liang, Chen; Shao, Chung‐Ping; Lai, Yi-Chi; Hor, Lien-I

doi:10.1093/infdis/jir070

Cited by 87 publications

(129 citation statements)

References 32 publications

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“…Although we could not predict the cell elongation factor of Vc450 from the proteome, we hypothesize that the RTX toxin is the most likely candidate as the cytotoxic substance, as it is a pore-forming toxin and the CHO cells were not completely lysed during the assay. In V. cholerae, RTX toxin acts as a virulence cofactor disrupting the cell wall integrity of the host cells (Olivier et al, 2007), whereas the V. vulnificus RTX toxin causes cell lysis through pore formation, resulting in the degradation of phagocytic host cells (Lo et al, 2011). An increased expression of RTX toxin in Vc450 at the virulent temperature of 27 1C may allow for increased survival of Vc450 owing to degradation of the host's innate immune system.…”

Section: Resultsmentioning

confidence: 99%

Temperature regulation of virulence factors in the pathogen Vibrio coralliilyticus

Kimes

Grim

Johnson³

et al. 2011

The ISME Journal

230

200

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Sea surface temperatures (SST) are rising because of global climate change. As a result, pathogenic Vibrio species that infect humans and marine organisms during warmer summer months are of growing concern. Coral reefs, in particular, are already experiencing unprecedented degradation worldwide due in part to infectious disease outbreaks and bleaching episodes that are exacerbated by increasing SST. For example, Vibrio coralliilyticus, a globally distributed bacterium associated with multiple coral diseases, infects corals at temperatures above 27 1C. The mechanisms underlying this temperature-dependent pathogenicity, however, are unknown. In this study, we identify potential virulence mechanisms using whole genome sequencing of V. coralliilyticus ATCC (American Type Culture Collection) BAA-450. Furthermore, we demonstrate direct temperature regulation of numerous virulence factors using proteomic analysis and bioassays. Virulence factors involved in motility, host degradation, secretion, antimicrobial resistance and transcriptional regulation are upregulated at the higher virulent temperature of 27 1C, concurrent with phenotypic changes in motility, antibiotic resistance, hemolysis, cytotoxicity and bioluminescence. These results provide evidence that temperature regulates multiple virulence mechanisms in V. coralliilyticus, independent of abundance. The ecological and biological significance of this temperature-dependent virulence response is reinforced by climate change models that predict tropical SST to consistently exceed 27 1C during the spring, summer and fall seasons. We propose V. coralliilyticus as a model Gram-negative bacterium to study temperature-dependent pathogenicity in Vibrio-related diseases.

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Section: Resultsmentioning

confidence: 99%

Temperature regulation of virulence factors in the pathogen Vibrio coralliilyticus

Kimes

Grim

Johnson³

et al. 2011

The ISME Journal

230

200

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“…To find out the role of rtxA1 3 in eel virulence, the authors performed in vivo experiments of colonization and invasion after infection through water, under the hypothesis that rtxA1 3 is an invasion factor as has been demonstrated for rtxA1 1 in the mouse (105). The double mutant in rtxA1 3 was able to attach to the gills and spread to the blood and internal organs, where it survived in numbers similar to those achieved by the wild type strain, but the eels were not killed.…”

Section: Toxinsmentioning

confidence: 99%

The Fish Pathogen Vibrio vulnificus Biotype 2: Epidemiology, Phylogeny, and Virulence Factors Involved in Warm-Water Vibriosis

et al. 2015

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Vibrio vulnificus biotype 2 is the etiological agent of warm-water vibriosis, a disease that affects eels and other teleosts, especially in fish farms. Biotype 2 is polyphyletic and probably emerged from aquatic bacteria by acquisition of a transferable virulence plasmid that encodes resistance to innate immunity of eels and other teleosts. Interestingly, biotype 2 comprises a zoonotic clonal complex designated as serovar E that has extended worldwide. One of the most interesting virulence factors produced by serovar E is RtxA1 3 , a multifunctional protein that acts as a lethal factor for fish, an invasion factor for mice, and a survival factor outside the host. Two practically identical copies of rtxA1 3 are present in all biotype 2 strains regardless of the serovar, one in the virulence plasmid and the other in chromosome II. The plasmid also contains other genes involved in survival and growth in eel blood: vep07, a gene for an outer membrane (OM) lipoprotein involved in resistance to eel serum and vep20, a gene for an OM receptor specific for eel-transferrin and, probably, other related fish transferrins. All the three genes are highly conserved within biotype 2, which suggests that they are under a strong selective pressure. Interestingly, the three genes are related with transferable plasmids, which emphasizes the role of horizontal gene transfer in the evolution of V. vulnificus in nutrient-enriched aquatic environments, such as fish farms.

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“…The ⌬luxO mutant was shown to be about 100-fold less virulent than the wild-type strain or luxO(D47E) mutant, and its spread into the bloodstream was much slower in mice infected subcutaneously (our unpublished data). These phenotypes of the ⌬luxO mutant are similar to those of an RTX-deficient mutant (15,19,21), suggesting a close association of LuxO with RTX-mediated cytotoxicity and virulence in mice.…”

Section: Discussionmentioning

confidence: 60%

“…In-frame deletions then were used to generate the specific gene knockout mutants. The ⌬rtxA1 mutants were isolated as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Cytotoxicity by Quorum-Sensing Signaling in Vibrio vulnificus Is Mediated by SmcR, a Repressor of hlyU

Shao

Lin

et al. 2011

J Bacteriol

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Cytotoxicity is an important virulence determinant in the pathogenesis of Vibrio vulnificus, and two cytotoxins, RTX (encoded by rtxA1) and cytolysin/hemolysin (encoded by vvhA), have been identified in this organism. We showed that the quorum-sensing regulator LuxO controlled the cytotoxicity of this organism: a ⌬luxO mutant exhibited low cytotoxicity, whereas a constitutively activated luxO mutant, luxO(D47E), remained highly cytotoxic. The cytotoxicity of the ⌬luxO mutant was restored when smcR, a Vibrio harveyi luxR homologue repressed by luxO, was further deleted. SmcR then was shown to repress the expression of both rtxA1 and vvhA. A DNA library of V. vulnificus was screened in Escherichia coli for clones that upregulated vvhA in the presence of SmcR, and hlyU, which has been shown to positively regulate rtxA1 and vvhA, was identified. We demonstrated that SmcR repressed the expression of hlyU and bound to a region upstream of hlyU in V. vulnificus. The deletion of hlyU resulted in the loss of cytotoxicity and reduced cytolysin/hemolysin production in the ⌬smcR mutant. The ⌬smcR ⌬hlyU mutant regained cytotoxicity and cytolysin/hemolysin activity when hns, which has been shown to repress the transcription of rtxA1 and interfere with hlyU, was further removed. Collectively, our data suggest that SmcR mediates the regulation of cytotoxicity by quorum-sensing signaling in V. vulnificus by repressing hlyU, an activator of rtxA1 and vvhA.Vibrio vulnificus, a Gram-negative marine bacterium, is an opportunistic pathogen causing septicemia and wound infection in humans; it has a high mortality rate, particularly in those who suffer from chronic liver diseases or are immunocompromised. This organism produces two major cytotoxins, cytolysin/hemolysin (encoded by vvhA) and RTX (repeats in toxin; encoded by rtxA1), that are implicated in its virulence (19,29). The cytolysin/hemolysin, which is an extracellular product, is lethal for mice at submicrogram levels. It lyses erythrocytes, increases vascular permeability (resulting in extensive extracellular edema in guinea pig skin), damages capillary endothelial cells, and causes mild inflammatory cell infiltration (7,8). The RTX toxin, which forms pores on cell membranes only after the contact of the bacterium with the host cell (12, 13), is required for V. vulnificus virulence in mice by promoting bacterial colonization at the infection site and subsequent invasion into the bloodstream (12, 15).Several regulators of vvhA and rtxA1 have been identified (1, 19). HlyU, which was identified by in vivo-induced antigen technology and is essential for V. vulnificus virulence in mice (11,19), is required for the expression of vvhA and rtxA1 and binds directly to a region upstream of the operon where rtxA1 is located (19,20).Quorum-sensing (QS) signaling, which is widely used by bacteria to communicate with each other, regulates the virulence genes in a variety of microorganisms, including Vibrio species (23, 30). In Vibrio cholerae, the signals transduced from at least three QS ...

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RTX Toxin Enhances the Survival of Vibrio vulnificus During Infection by Protecting the Organism From Phagocytosis

Cited by 87 publications

References 32 publications

Temperature regulation of virulence factors in the pathogen Vibrio coralliilyticus

Temperature regulation of virulence factors in the pathogen Vibrio coralliilyticus

The Fish Pathogen Vibrio vulnificus Biotype 2: Epidemiology, Phylogeny, and Virulence Factors Involved in Warm-Water Vibriosis

Regulation of Cytotoxicity by Quorum-Sensing Signaling in Vibrio vulnificus Is Mediated by SmcR, a Repressor of hlyU

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