VvpE mediates the intestinal colonization of Vibrio vulnificus by the disruption of tight junctions

Lee, Sei-Jung; Jung, Young Hyun; Ryu, Jung Min; Jang, Kyung Ku; Choi, Sang Ho; Han, Ho Jae

doi:10.1016/j.ijmm.2015.10.006

Cited by 22 publications

(16 citation statements)

References 42 publications

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“…vulnificus elastase product of vvpE modulates paracellular permeability by altering tight junction protein dynamics [41]. However here no significant dysfunction is observed in monolayers exposed to ΔvvhA ΔrtxA1 , indicating that vvpE does not increase permeability or intestinal damage in this context.…”

Section: Discussionmentioning

confidence: 76%

“…Notably, some vvhA- and rtxA1- independent virulence was observed at these high-doses. This could be due to bacterial components, such as LPS, and/or minor virulence factors, such as the VvpE metalloprotease, all of which may influence pathogenesis at very high dose in the absence of dominant virulence factors [40, 41]. Nonetheless, the ΔvvhA rtxA1 :: bla strain does not confer additional virulence over the null mutant [18].…”

Section: Resultsmentioning

confidence: 99%

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The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

2017

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Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin’s central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD) in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity. We previously reported that the native MARTX toxin effector domain repertoire is dispensable for epithelial cellular necrosis in vitro, but essential for cell rounding and apoptosis prior to necrotic cell death. Here we use an intragastric mouse model to demonstrate that the effector domain region is required for bacterial virulence during intragastric infection. The MARTX effector domain region is essential for bacterial dissemination from the intestine, but dissemination occurs in the absence of overt intestinal tissue pathology. We employ an in vitro model of V. vulnificus interaction with polarized colonic epithelial cells to show that the MARTX effector domain region induces rapid intestinal barrier dysfunction and increased paracellular permeability prior to onset of cell lysis. Together, these results negate the inherent assumption that observations of necrosis in vitro directly predict bacterial virulence, and indicate a paradigm shift in our conceptual understanding of MARTX toxin function during intestinal infection. Results implicate the MARTX effector domain region in mediating early bacterial dissemination from the intestine to distal organs–a key step in V. vulnificus foodborne pathogenesis–even before onset of overt intestinal pathology.

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Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

2017

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“…The recovered bacterial cells were enumerated as cfu/100 l of blood. The remaining blood samples were used for hematological analyses, as described previously (63). Briefly, MPXI was analyzed by using a hematological autoanalyzer (AVIDA 2120, Bayer Diagnostics, Giessen, Germany).…”

Section: Mouse Infection Experimentsmentioning

confidence: 99%

Identification and characterization of Vibrio vulnificus plpA encoding a phospholipase A2 essential for pathogenesis

Jang¹,

Lee²,

Kim³

et al. 2017

Journal of Biological Chemistry

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The marine bacterium causes food-borne diseases, which may lead to life-threatening septicemia in some individuals. Therefore, identifying virulence factors in is of high priority. We performed a transcriptome analysis on after infection of human intestinal HT29-methotrexate cells and found induction of, encoding a putative phospholipase, PlpA. Bioinformatics, biochemical, and genetic analyses demonstrated thatPlpA is a phospholipase A secreted in a type II secretion system-dependent manner. Compared with the wild type, the mutant exhibited reduced mortality, systemic infection, and inflammation in mice as well as low cytotoxicity toward the human epithelial INT-407 cells. Moreover, mutation attenuated the release of actin and cytosolic cyclophilin A from INT-407 cells, indicating that PlpA is a virulence factor essential for causing lysis and necrotic death of the epithelial cells. transcription was growth phase-dependent, reaching maximum levels during the early stationary phase. Also, transcription factor HlyU and cAMP receptor protein (CRP) mediate additive activation and host-dependent induction of Molecular biological analyses revealed that expression is controlled via the promoter, P , and that HlyU and CRP directly bind to P upstream sequences. Taken together, this study demonstrated that PlpA is a type II secretion system-dependent secretory phospholipase A regulated by HlyU and CRP and is essential for the pathogenicity of .

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“…Previous mouse colonization assays demonstrated that V. vulnificus initially and mostly colonizes in the small intestine and disseminates to other organs (37,38). Therefore, colonization of each strain in the mouse small intestine was determined by competition assays as described previously (30).…”

Section: Methodsmentioning

confidence: 99%

Regulatory Characteristics of Vibrio vulnificus gbpA Gene Encoding a Mucin-binding Protein Essential for Pathogenesis

Jang

Gil

Lim

et al. 2016

Journal of Biological Chemistry

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Binding to mucin is the initial step for enteropathogens to establish pathogenesis. An open reading frame, gbpA, of Vibrio vulnificus was identified and characterized in this study. Compared with wild type, the gbpA mutant was impaired in binding to mucin-agar and the mucin-secreting HT29-methotrexate cells, and the impaired mucin binding was restored by the purified GbpA provided exogenously. The gbpA mutant had attenuated virulence and ability of intestinal colonization in a mouse model, indicating that GbpA is a mucin-binding protein and essential for pathogenesis of V. vulnificus. The gbpA transcription was growth phase-dependent, reaching a maximum during the exponential phase. The Fe-S cluster regulator (IscR) and the cyclic AMP receptor protein (CRP) coactivated, whereas SmcR, a LuxR homologue, repressed gbpA. The cellular levels of IscR, CRP, and SmcR were not significantly affected by one another, indicating that the regulator proteins function cooperatively to regulate gbpA rather than sequentially in a regulatory cascade. The regulatory proteins directly bind upstream of the gbpA promoter P gbpA . DNase I protection assays, together with the deletion analyses of P gbpA , demonstrated that IscR binds to two specific sequences centered at ؊164.5 and ؊106, and CRP and SmcR bind specifically to the sequences centered at ؊68 and ؊45, respectively. Furthermore, gbpA was induced by exposure to H 2 O 2 , and the induction appeared to be mediated by elevated intracellular levels of IscR. Consequently, the combined results indicated that IscR, CRP, and SmcR cooperate for precise regulation of gbpA during the V. vulnificus pathogenesis.

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VvpE mediates the intestinal colonization of Vibrio vulnificus by the disruption of tight junctions

Cited by 22 publications

References 42 publications

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

Identification and characterization of Vibrio vulnificus plpA encoding a phospholipase A2 essential for pathogenesis

Regulatory Characteristics of Vibrio vulnificus gbpA Gene Encoding a Mucin-binding Protein Essential for Pathogenesis

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