RtxA1‐Induced Expression of the Small GTPase Rac2 Plays a Key Role in the Pathogenicity of<i>Vibrio vulnificus</i>

Chung, Kyoung‐Jin; Cho, Eunjin; Kim, Mi Kwang; Kim, Young Ran; Kim, Seokho; Yang, Hee‐Young; Chung, Ki-Chul; Lee, Shee Eun; Rhee, Joon Haeng; Choy, Hyon E.; Lee, Tae‐Hoon

doi:10.1086/648612

Cited by 48 publications

(40 citation statements)

References 32 publications

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“…It has been reported that ROS induce the expression of E. coli iscR (9,10,12), and the host epithelial cells infected with V. vulnificus generate ROS (28). Therefore, we hypothesized that the induction of iscR expression upon exposure to INT-407 cells could result from the increased level of ROS generated from the host cells.…”

Section: Effects Of Host Cells On Iscr Expression Expression Of Iscrmentioning

confidence: 97%

“…When necessary, the wild-type V. vulnificus grown to A 600 0.5 was exposed to MEMF (control), hydrogen peroxide (H 2 O 2 ), INT-407 cells, or INT-407 cells preincubated with 25 mM N-acetyl-L-cysteine (NAC) for 1 h to scavenge reactive oxygen species (ROS) (28). For H 2 O 2 exposure experiments, V. vulnificus was grown anaerobically as described elsewhere (29).…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

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IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Lim

Choi

2014

Infect Immun

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A mutant that exhibited less cytotoxic activity toward INT-407 human intestinal epithelial cells than the wild type was screened from a random transposon mutant library of Vibrio vulnificus, and an open reading frame encoding an Fe-S cluster regulator, IscR, was identified using a transposon-tagging method. A mutational analysis demonstrated that IscR contributes to mouse mortality as well as cytotoxicity toward the INT-407 cells, indicating that IscR is essential for the pathogenesis of V. vulnificus. A whole-genome microarray analysis revealed that IscR influenced the expression of 67 genes, of which 52 were upregulated and 15 were downregulated. Among these, 12 genes most likely involved in motility and adhesion to host cells, hemolytic activity, and survival under oxidative stress of the pathogen during infection were selected and experimentally verified to be upregulated by IscR. Accordingly, the disruption of iscR resulted in a significant reduction in motility and adhesion to INT-407 cells, in hemolytic activity, and in resistance to reactive oxygen species (ROS) such as H 2 O 2 and tert-butyl hydroperoxide (t-BOOH). Furthermore, the present study demonstrated that iscR expression was induced by exposure of V. vulnificus to the INT-407 cells, and the induction appeared to be mediated by ROS generated by the host cells during infection. Consequently, the combined results indicated that IscR is a global regulator that contributes to the overall success in the pathogenesis of V. vulnificus by regulating the expression of various virulence and survival genes in addition to Fe-S cluster genes. Most of virulence factors of pathogenic bacteria act cooperatively to obtain maximum effectiveness during pathogenesis while their expression is coordinately regulated by common global regulators in response to environmental conditions, and this coordinated regulation facilitates the cooperation of virulence factors and is crucial to the overall success of the pathogens during infection (1, 2). Vibrio vulnificus is an opportunistic Gram-negative pathogen that frequently contaminates oysters. It has been proposed that numerous virulence factors account for the fulminating and destructive nature of V. vulnificus infections and contribute to not only disease development but also the survival and multiplication on or within the host (for a recent review, see reference 3). However, studies about global regulators involved in the regulation of V. vulnificus virulence factors are still very limited.Iron-sulfur proteins containing the Fe-S cluster as a cofactor carry out multiple important cellular processes such as electron transfer, metabolic reactions, and gene regulation and are widely distributed (for recent reviews, see references 4 and 5). A highly conserved isc operon, iscRSUA-hscBA-fdx, was discovered to encode all of the proteins required for the biogenesis of the majority, if not all, of the Fe-S cluster proteins in Escherichia coli (for recent reviews, see references 5 and 6). Expression of the isc operon is autoregu...

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Section: Effects Of Host Cells On Iscr Expression Expression Of Iscrmentioning

confidence: 97%

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Lim

Choi

2014

Infect Immun

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“…This attenuated virulence of the prx3 mutant suggested that Prx3 is essential for the pathogenesis of V. vulnificus. Recent work also has shown that the cells of mouse intestine infected with V. vulnificus generate ROS (45). Therefore, it is reasonable to assume that Prx3 could contribute to the pathogenesis by protecting the pathogen from the ROS imposed by host cells to ensure its survival and multiplication during infection.…”

Section: Prx3 Is Essential For Survival Under Oxidative Stress and VImentioning

confidence: 99%

Characterization of the Vibrio vulnificus 1-Cys Peroxiredoxin Prx3 and Regulation of Its Expression by the Fe-S Cluster Regulator IscR in Response to Oxidative Stress and Iron Starvation

Lim

Bang

Choi

2014

Journal of Biological Chemistry

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Background: ROS and iron availability influence [2Fe-2S] cluster occupancy in IscR.Results: Prx3 is a Grx3/glutathione-dependent 1-Cys peroxiredoxin essential for survival under oxidative stress and pathogenesis of Vibrio vulnificus, and IscR directly activates prx3 by sensing ROS and iron starvation. Conclusion: IscR-dependent prx3 expression contributes to the pathogenesis of V. vulnificus. Significance: This study elucidated the IscR-mediated regulation of an antioxidant enzyme.

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“…In fact, V. vulnificus accounts for 1% of all food-related deaths in the United States (4). Numerous studies recently have described a V. vulnificus multifunctional-autoprocessing RTX toxin (MARTX Vv ) as having a major impact on virulence in mice (5)(6)(7)(8). Toxins of the MARTX family are very large composite toxins.…”

mentioning

confidence: 99%

Vibrio vulnificus rtxA1 gene recombination generates toxin variants with altered potency during intestinal infection

Kwak

Jeong

Satchell

2011

Proc. Natl. Acad. Sci. U.S.A.

143

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Vibrio vulnificus is a food-borne bacterial pathogen associated with 1% of all food-related deaths, predominantly because of consumption of contaminated seafood. The ability of V. vulnificus to cause disease is linked to the production of a large cytotoxin called the "multifunctional-autoprocessing RTX" (MARTX Vv ) toxin, a factor shown here to be an important virulence factor by the intragastric route of infection in mice. In this study, we examined genetic variation of the rtxA1 gene that encodes MARTX Vv in 40 V. vulnificus Biotype 1 strains and found four distinct variants of rtxA1 that encode toxins with different arrangements of effector domains. We provide evidence that these variants arose by recombination either with rtxA genes carried on plasmids or with the rtxA gene of Vibrio anguillarum. Contrary to expected results, the most common rtxA1 gene variant in clinical-type V. vulnificus encodes a toxin with reduced potency and is distinct from the toxin produced by strains isolated from market oysters. These results indicate that an important virulence factor of V. vulnificus is undergoing significant genetic rearrangement and may be subject to selection for reduced virulence in the environment. This finding would imply further that in the future on-going genetic variation of the MARTX Vv toxins could result in the emergence of novel strains with altered virulence in humans.phylogeny | RTX | oyster T he gram-negative bacterial pathogen Vibrio vulnificus inhabits coastal waters including the US Gulf Coast. The pathogen causes gastroenteritis, primary septicemia, and necrotizing fasciitis and can be difficult to treat. The bacteria are particularly rapid growers in vivo and are highly invasive; thus death can occur as quickly as 24-48 h after ingestion (1, 2). In the United States from 1998-2008, 985 cases of V. vulnificus infection resulting in 91 deaths were reported to the Centers for Disease Control. Of these cases, 60% were caused by food-borne illness, particularly associated with the consumption of raw seafood (3). In fact, V. vulnificus accounts for 1% of all food-related deaths in the United States (4). Numerous studies recently have described a V. vulnificus multifunctional-autoprocessing RTX toxin (MARTX Vv ) as having a major impact on virulence in mice (5-8). Toxins of the MARTX family are very large composite toxins. The 5,206-amino acid MARTX Vv toxin as found in the two sequenced strains of V. vulnificus, Korean isolate CMCP6 and Taiwanese isolate YJ016 (9, 10), are 99% identical. Similar to all MARTX toxins, the majority of MARTX Vv is comprised of conserved repeat regions at the N and C termini that are proposed to form a pore in the eukaryotic cell plasma membrane for translocation of the central portion of the secreted toxin to the cytosol (11). The central region includes a conserved cysteine protease domain (CPD) that is required for inositol hexakisphosphate-induced autoprocessing. After translocation, autoprocessing at leucine residues in unstructured regions between the effector do...

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RtxA1‐Induced Expression of the Small GTPase Rac2 Plays a Key Role in the Pathogenicity ofVibrio vulnificus

Cited by 48 publications

References 32 publications

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Characterization of the Vibrio vulnificus 1-Cys Peroxiredoxin Prx3 and Regulation of Its Expression by the Fe-S Cluster Regulator IscR in Response to Oxidative Stress and Iron Starvation

Vibrio vulnificus rtxA1 gene recombination generates toxin variants with altered potency during intestinal infection

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