Survival of<i>Vibrio vulnificus</i>in Whole Blood from Patients with Chronic Liver Diseases: Association with Phagocytosis by Neutrophils and Serum Ferritin Levels

Hor, Lien-I; Chang, Ting‐Tsung; Wang, Shan‐Tair

doi:10.1086/314554

Cited by 79 publications

(57 citation statements)

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“…Consistent with our data, neutropenic mice have been shown to exhibit significantly increased sensitivity to V. vulnificus infection (21). Furthermore, the phagocytic activity of neutrophils in patients with chronic liver diseases has been shown to be lower than that in healthy individuals, and survival of V. vulnificus in these patients was shown to be inversely correlated with the extent of neutrophil-mediated phagocytosis (47). Given that V. vulnificus RtxA1/MARTX Vv can be delivered by direct contact of the bacteria with the target cells, we hypothesize that 47RA might target the RtxA1/MARTX Vv from V. vulnificus attached to target cells, such as neutrophils.…”

Section: Discussionsupporting

confidence: 89%

Monoclonal Antibodies against Vibrio vulnificus RtxA1 Elicit Protective Immunity through Distinct Mechanisms

et al. 2014

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g Vibrio vulnificus causes rapidly progressing septicemia with an extremely high mortality rate (>50%), even with aggressive antibiotic treatment. The bacteria secrete multifunctional autoprocessing repeats-in-toxin (MARTX) toxins, which are involved in the pathogenesis of Gram-negative Vibrio species. Recently, we reported that immunization with the C-terminal region of V. vulnificus RtxA1/MARTX Vv , RtxA1-C, elicits a protective immune response against V. vulnificus through a poorly defined mechanism. In this study, we generated a panel of new monoclonal antibodies (MAbs) against V. vulnificus RtxA1-C and investigated their protective efficacies and mechanisms in a mouse model of infection. Prophylactic administration of seven MAbs strongly protected mice against lethal V. vulnificus infection (more than 90% survival). Moreover, three of these MAbs (21RA, 24RA, and 47RA) demonstrated marked efficacy as postexposure therapy. Notably, 21RA was therapeutically effective against lethal V. vulnificus infection by a variety of routes. Using Fab fragments and a neutropenic mouse model, we showed that 21RA and 24RA mediate protection from V. vulnificus infection through an Fc-independent and/or neutrophil-independent pathway. In contrast, 47RA-mediated protection was dependent on its Fc region and was reduced to 50% in neutropenic mice compared with 21RA-mediated and 24RA-mediated protection. Bacteriological study indicated that 21RA appears to enhance the clearance of V. vulnificus from the blood. Overall, these studies suggest that humoral immunity controls V. vulnificus infection through at least two different mechanisms. Furthermore, our panel of MAbs could provide attractive candidates for the further development of immunoprophylaxis/therapeutics and other therapies against V. vulnificus that target the MARTX toxin.V ibrio vulnificus, a member of the normal marine microbiota, is an important human pathogen associated with the consumption of seafood and wound infection following exposure to water containing this pathogen (1-4). The bacterial infection frequently progresses to severe skin lesions and septicemia in people with hepatic disorders or immunocompromised conditions (5). Despite support care and aggressive antibiotic therapy, V. vulnificus septicemia has a greater than 50% mortality rate; this rate increases to more than 90% for patients with septic shock (5-8). During the past decade, the incidence of V. vulnificus infection has increased worldwide, probably due to the warming of coastal waters (9, 10).V. vulnificus produces a wide range of potential virulence factors required for survival and growth, including capsular polysaccharide (VvPS), iron assimilation systems, flagella, pili, VvhA, VvpE, and the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin (MARTX Vv , or RtxA1) (8, 11). Among them, V. vulnificus RtxA1/MARTX Vv , a large secreted protein, belongs to the repeats-in-toxin (RTX) toxin family, which has been identified in a number of Gram-negative bacterial pathogens (12, 13). V. vuln...

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Section: Discussionsupporting

confidence: 89%

Monoclonal Antibodies against Vibrio vulnificus RtxA1 Elicit Protective Immunity through Distinct Mechanisms

et al. 2014

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“…At 6 h after infection, the wild type was recovered at levels of 3.6 ϫ 10 5 /ml of blood, whereas the R62H/D77N mutant was recovered at levels approximately 4 log orders lower than the wild type. Live R62H/ D77N cells were completely cured from the bloodstream 24 h after infection, whereas the isogenic wild-type strain killed all of the infected mice within 10 h. These results indicate that the R62H/D77N mutant entered into the bloodstream could not replicate well and was eventually removed by the innate immune system such as serum bactericidal activity and mononuclear phagocytes (13,22,32,35). Wild-type V. vulnificus seemed to replicate robustly in mice.…”

Section: Vol 75 2007 In Vivo-expressed Survival Factor Pyrh 2799mentioning

confidence: 96%

The pyrH Gene of Vibrio vulnificus Is an Essential In Vivo Survival Factor

Lee

Kim

et al. 2007

Infect Immun

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We have suggested an important role of the pyrH gene during the infectious process of Vibrio vulnificus. Previously, we have identified 12 genes expressed preferentially during human infections by using in vivoinduced antigen technology. Among the in vivo-expressed genes, pyrH encodes UMP kinase catalyzing UMP phosphorylation. Introduction of a deletion mutation to the pyrH gene was lethal to V. vulnificus, and an insertional mutant showed a high frequency of curing. We constructed a site-directed mutant strain (R62H/ D77N) on Arg-62 and Asp-77, both predicted to be involved in UMP binding, and characterized the R62H/D77N strain compared with the previously reported insertional mutant. We further investigated the essential role of the pyrH gene in the establishment of infection using the R62H/D77N strain. Cytotoxicity was decreased in the R62H/D77N strain, and the defect was restored by an in trans complementation. The intraperitoneal 50% lethal dose of the R62H/D77N strain increased by 26-and 238,000-fold in normal and iron-overloaded mice, respectively. The growth of the R62H/D77N strain in 50% HeLa cell lysate, 100% human ascitic fluid, and 50% human serum was significantly retarded compared to that of the isogenic wild-type strain. The R62H/D77N mutant also had a critical defect in the ability to survive and replicate even in iron-overloaded mice. These results demonstrate that pyrH is essential for the in vivo survival and growth of V. vulnificus and should be an attractive new target for the development of antibacterial drugs and replication-controllable live attenuated vaccines.Vibrio vulnificus is an estuarine bacterium that opportunistically infects a human being through the consumption of contaminated seafood or wound infection. V. vulnificus septicemia preferentially occurs in patients with underlying hepatic diseases or other immunocompromised conditions and results in a rapid progress and high mortality rate of Ͼ50% (10,22,35). During the infectious process, the V. vulnificus is confronted with dramatic environmental changes, and the bacteria seem to cognitively sense the changes in the host milieu. For the successful infection, V. vulnificus should establish coordinated spatiotemporal expression of various virulence genes in vivo (11, 12). Our group has previously reported 12 in vivo expressed genes by using in vivo-induced antigen technology (17). Among them, pyrH encodes UMP kinase, which catalyzes phosphorylation of UMP to UDP (24, 26). It was reported that UMP kinase senses the environmental pyrimidine pool and directly regulates pyrimidine-specific CarP1 promoter of carbamoylphosphate synthetase of Escherichia coli responsible for the early stage de novo synthesis of pyrimidines (15). Klarsfeld et al. have reported that pyrE of Listeria monocytogenes, another de novo pyrimidine biosynthetic gene, preferentially expressed the intracellular milieu of host cells through a transposon mutant library screening experiment (18). These previous reports suggest that limited availability of pyrimidines i...

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“…Capsular polysaccharide (CPS) and exopolysaccharide (EPS) are important virulence and adhesion factors for many pathogens. CPS mediates resistance of bacteria to complement-mediated bacteriolysis and phagocytosis (31,34). EPS possesses both adsorptive and adhesive properties (6,42,89).…”

mentioning

confidence: 99%

Identification of a c-di-GMP-Regulated Polysaccharide Locus Governing Stress Resistance and Biofilm and Rugose Colony Formation in Vibrio vulnificus

Guo

Rowe‐Magnus

2010

Infect Immun

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As an etiological agent of bacterial sepsis and wound infections, Vibrio vulnificus is unique among the Vibrionaceae. Its continued environmental persistence and transmission are bolstered by its ability to colonize shellfish, form biofilms on various marine biotic surfaces, and generate a morphologically and physiologically distinct rugose (R) variant that yields profuse biofilms. Here, we identify a c-di-GMP-regulated locus (brp, for biofilm and rugose polysaccharide) and two transcription factors (BrpR and BrpT) that regulate these physiological responses. Disruption of glycosyltransferases within the locus or either regulator abated the inducing effect of c-di-GMP on biofilm formation, rugosity, and stress resistance. The same lesions, or depletion of intracellular c-di-GMP levels, abrogated these phenotypes in the R variant. The parental and brp mutant strains formed only scant monolayers on glass surfaces and oyster shells, and although the R variant formed expansive biofilms, these were of limited depth. Dramatic vertical expansion of the biofilm structure was observed in the parental strain and R variant, but not the brp mutants, when intracellular c-di-GMP levels were elevated. Hence, the brp-encoded polysaccharide is important for surface colonization and stress resistance in V. vulnificus, and its expression may control how the bacteria switch from a planktonic lifestyle to colonizing shellfish to invading human tissue.

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Survival ofVibrio vulnificusin Whole Blood from Patients with Chronic Liver Diseases: Association with Phagocytosis by Neutrophils and Serum Ferritin Levels

Cited by 79 publications

References 10 publications

Monoclonal Antibodies against Vibrio vulnificus RtxA1 Elicit Protective Immunity through Distinct Mechanisms

Monoclonal Antibodies against Vibrio vulnificus RtxA1 Elicit Protective Immunity through Distinct Mechanisms

The pyrH Gene of Vibrio vulnificus Is an Essential In Vivo Survival Factor

Identification of a c-di-GMP-Regulated Polysaccharide Locus Governing Stress Resistance and Biofilm and Rugose Colony Formation in Vibrio vulnificus

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