Mechanism of High Susceptibility of Iron‐Overloaded Mouse to <i>Vibrio vulnificus</i> Infection

Hor, Lien-I; Chang, Yir-kun; Chang, Chien‐Chung; Lei, Huan‐Yao; Ou, Jonathan T.

doi:10.1111/j.1348-0421.2000.tb02577.x

Cited by 72 publications

(57 citation statements)

References 23 publications

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“…Bacterial virulence in mice was determined in C3H/HeN mice (6 to 8 weeks old, purchased from the Animal Center of College of Medicine, National ChengKung University) infected by intraperitoneal injection (26). Four 10-fold serially diluted doses were used for each strain, and five mice were challenged per dose.…”

Section: Methodsmentioning

confidence: 99%

A Common Virulence Plasmid in Biotype 2 Vibrio vulnificus and Its Dissemination Aided by a Conjugal Plasmid

Lee

Amaro

et al. 2008

J Bacteriol

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Strains of Vibrio vulnificus, a marine bacterial species pathogenic for humans and eels, are divided into three biotypes, and those virulent for eels are classified as biotype 2. All biotype 2 strains possess one or more plasmids, which have been shown to harbor the biotype 2-specific DNA sequences. In this study we determined the DNA sequences of three biotype 2 plasmids: pR99 (68.4 kbp) in strain CECT4999 and pC4602-1 (56.6 kb) and pC4602-2 (66.9 kb) in strain CECT4602. Plasmid pC4602-2 showed 92% sequence identity with pR99. Curing of pR99 from strain CECT4999 resulted in loss of resistance to eel serum and virulence for eels but had no effect on the virulence for mice, an animal model, and resistance to human serum. Plasmids pC4602-2 and pR99 could be transferred to the plasmid-cured strain by conjugation in the presence of pC4602-1, which was self-transmissible, and acquisition of pC4602-2 restored the virulence of the cured strain for eels. Therefore, both pR99 and pC4602-2 were virulence plasmids for eels but not mice. A gene in pR99, which encoded a novel protein and had an equivalent in pC4602-2, was further shown to be essential, but not sufficient, for the resistance to eel serum and virulence for eels. There was evidence showing that pC4602-2 may form a cointegrate with pC4602-1. An investigation of six other biotype 2 strains for the presence of various plasmid markers revealed that they all harbored the virulence plasmid and four of them possessed the conjugal plasmid in addition.Vibrio vulnificus is a gram-negative bacterial species that is ubiquitous in marine environments. This organism causes infections that are characterized by severe wound infection and primary septicemia with high mortality in humans, particularly those with underlying diseases such as liver cirrhosis and hemochromatosis (33,40). It also causes systemic infections, called vibriosis, with high mortality in brackish-water-cultured eels (4, 16). This organism is considered an emerging pathogen, since cases in fish and human were first reported in 1976 and 1979, respectively (8, 34).Strains of V. vulnificus are divided into three biotypes, biotype 1 (BT1), BT2, and BT3, based on their differences in phenotypic traits, serological type, and host range (6, 7, 42). All three biotypes can cause sporadic cases of human diseases and have been shown to be virulent for the mouse, an animal model; however, only the BT2 strains produce epizootic or outbreaks of vibriosis, mainly in eels (4, 34). The lesions on the body of a V. vulnificus-infected eel, similar to those caused by Vibrio anguillarum, include external skin ulcer, hemorrhagic fins, protrusion of the rectum, and hemorrhages and inflammation of the internal organs (4). The BT2 strains are further subdivided into several serovars (6,16,22), among which serovar E is not only the most virulent and prevalent but also the only one isolated from sporadic human infections associated with handling of contaminated fish (1).The virulence mechanism of BT2 V. vulnificus strains in eels rem...

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Section: Methodsmentioning

confidence: 99%

A Common Virulence Plasmid in Biotype 2 Vibrio vulnificus and Its Dissemination Aided by a Conjugal Plasmid

Lee

Amaro

et al. 2008

J Bacteriol

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“…In epidemiological studies, primary septicemia caused by V. vulnificus is most often associated with preexisting liver disease, although other conditions, such as diabetes mellitus, hemochromatosis, immunodeficiency, or malignancy, may also increase susceptibility to this organism (2,14,17,24,41). The impairment of iron metabolism and resultant iron overload associated with many of these conditions is thought to support increased V. vulnificus growth and reduced immune clearance (1,15,16). Primary septicemia caused by V. vulnificus appears to follow a classical septic shock pathway, including an overwhelming inflammatory cytokine response followed by multiorgan failure and death.…”

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Inflammatory Cytokine Response to Vibrio vulnificus Elicited by Peripheral Blood Mononuclear Cells from Chronic Alcohol Users Is Associated with Biomarkers of Cellular Oxidative Stress

et al. 2003

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Vibrio vulnificus is the leading cause of death in the United States associated with the consumption of raw seafood, particularly oysters. In epidemiological studies, primary septicemia and inflammation-mediated septic shock caused by V. vulnificus is strongly associated with liver disease, often in the context of chronic alcohol abuse. The present study was undertaken to determine whether clinical biomarkers of liver function or cellular oxidative stress are associated with peripheral blood mononuclear cell inflammatory cytokine responses to V. vulnificus. Levels of interleukin-1␤ (IL-1␤), IL-6, IL-8, and tumor necrosis factor alpha elicited in response to V. vulnificus and measured in cell supernatants were not associated with the liver biomarkers aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or the AST/ALT ratio. Vibrio vulnificus is a gram-negative bacterium found commonly in marine and estuarine environments. In the United States, it predominates in the warm waters of the Gulf and Atlantic Coasts (25, 27, 28). Despite not being a notifiable disease, each year there are 20 to 50 reported cases of V. vulnificus primary septicemia in the United States, occurring most often following the consumption of naturally contaminated raw oysters (2, 14). V. vulnificus also has the ability to cause gastroenteritis, which is generally self-limiting, and wound infections in otherwise healthy individuals (17, 32). Primary septicemia is seen almost exclusively in people with an underlying condition affecting their immune system. In epidemiological studies, primary septicemia caused by V. vulnificus is most often associated with preexisting liver disease, although other conditions, such as diabetes mellitus, hemochromatosis, immunodeficiency, or malignancy, may also increase susceptibility to this organism (2,14,17,24,41). The impairment of iron metabolism and resultant iron overload associated with many of these conditions is thought to support increased V. vulnificus growth and reduced immune clearance (1, 15, 16). Primary septicemia caused by V. vulnificus appears to follow a classical septic shock pathway, including an overwhelming inflammatory cytokine response followed by multiorgan failure and death. Presently, there is no effective treatment for V. vulnificus once someone has developed primary septicemia, and death usually ensues. It should be noted that V. vulnificus has many similarities with other gram-negative, encapsulated, opportunistic bacterial pathogens and likely exploits similar host susceptibility pathways that could be targeted for intervention.To date, the majority of V. vulnificus studies have focused on the bacterial factors involved in disease (41). Therefore, while much is now known about some of the bacterial factors involved in the disease process, little is understood about host cellular factors leading to susceptibility. It has been previously shown that V. vulnificus has the ability to elicit inflammationassociated cytokines from primary human cells in vitro and from animals...

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“…[4][5][6][7][8] VVS pathogenesis is promoted by the elevated serum iron levels, and crucially requires the assimilation of iron from transferrins by V. vulnificus. 9) V. vulnificus is known to produce two types of siderophores: catechol-and hydroxamate-siderophores.…”

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Vibrio vulnificus Vulnibactin, But Not Metalloprotease VvpE, Is Essentially Required for Iron-Uptake from Human Holotransferrin

Kim

Park

et al. 2006

Biological & Pharmaceutical Bulletin

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Vibrio vulnificus is a gram-negative halophilic estuarine bacterium. The pathogen causes fatal and rapidly-progressing septicemia with high mortality. This V. vulnificus septicemia (VVS) is closely associated with the consumption of raw seafood contaminated with the bacterium in patients with underlying hepatic disease, heavy alcohol-drinking habits, or other immunocompromised conditions. Several putative virulence factors including capsule, hemolysin, protease, and iron-assimilation systems have been suggested to be associated with VVS, but only capsule and iron-assimilation systems have been confirmed to be authentic virulence factors, in accordance with the molecular version of Koch's postulates. 1-3)It has also been well documented that iron and iron-assimilation systems play a crucial role in the pathogenesis of VVS. [4][5][6][7][8] VVS pathogenesis is promoted by the elevated serum iron levels, and crucially requires the assimilation of iron from transferrins by V. vulnificus. 9) V. vulnificus is known to produce two types of siderophores: catechol-and hydroxamate-siderophores. 10) Of these, the catechol-siderophore (called vulnibactin) is known to play the more important role in iron-uptake from transferrins and the virulence of V. vulnificus. [10][11][12][13][14] Expression of the vulnibactin-mediated iron-uptake system is regulated by Fur, a repressor regulating iron uptake. Both the mutation of venB gene encoding an enzyme required for vulnibactin synthesis and the mutation of vuuA gene encoding vulnibactin receptor protein can abolish the ability of V. vulnificus to assimilate iron from transferrins and to grow on holotransferrin (HT).In addition, a metalloprotease (named VvpE) of V. vulnificus has been extensively studied, and is known to exert a variety of biological effects.1-3,15,16) However, the role of VvpE in the pathogenesis of VVS remains unclear, as VvpE-deficient mutants showed comparable or higher virulence than wild type strains in mouse experimental models. [17][18][19] Of the various biological activities of VvpE, its role in facilitating V. vulnificus iron-uptake via the proteolytic cleavage of heme proteins, transferrins, and lactoferrins has attracted some attention. 15,16) However, our previous study demonstrated that an insertional mutation of vvpE gene has no direct effect on iron-assimilation from human transferrins. 20)Bacterial iron-uptake systems are themselves virulence factors in many bacterial pathogens, and are promising vaccine targets.21) Also, iron-chelation is considered a prospective therapeutic means of preventing in vivo bacterial growth. 22) In these regards, it is of considerable importance that bacterial iron-uptake mechanisms be evaluated. However, the roles of vulnibactin and VvpE in V. vulnificus ironuptake from transferrins have been determined using different methods under different experimental conditions. [11][12][13]20) Therefore, we considered that a definitive comparison and reevaluation of the roles of VvpE and vulnibactin is required, i.e., using the ...

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Mechanism of High Susceptibility of Iron‐Overloaded Mouse to Vibrio vulnificus Infection

Cited by 72 publications

References 23 publications

A Common Virulence Plasmid in Biotype 2 Vibrio vulnificus and Its Dissemination Aided by a Conjugal Plasmid

A Common Virulence Plasmid in Biotype 2 Vibrio vulnificus and Its Dissemination Aided by a Conjugal Plasmid

Inflammatory Cytokine Response to Vibrio vulnificus Elicited by Peripheral Blood Mononuclear Cells from Chronic Alcohol Users Is Associated with Biomarkers of Cellular Oxidative Stress

Vibrio vulnificus Vulnibactin, But Not Metalloprotease VvpE, Is Essentially Required for Iron-Uptake from Human Holotransferrin

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