Ferrophilic Characteristics of<i>Vibrio vulnificus</i>and Potential Usefulness of Iron Chelation Therapy

Kim, Choon-Mee; Park, Ra-Young; Choi, Mihwa; Sun, Haibin; Shin, Sung‐Heui

doi:10.1086/509822

Cited by 38 publications

(39 citation statements)

References 39 publications

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“…1 cell of V. vulnificus. Studies by Kim et al (7) concluded that V. vulnificus requires high levels of readily available non-transferrin-bound iron for the initiation of growth. V. vulnificus is known to produce two classes of iron-scavenging siderophores, catechol and hydroxymate, which allow for the use of transferrin-bound iron (7,11,13,19,20).…”

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Role of Iron in Human Serum Resistance of the Clinical and Environmental Vibrio vulnificus Genotypes

Bogard

Oliver

2007

Appl Environ Microbiol

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We recently reported a simple PCR procedure that targets a sequence variation of the virulencecorrelated gene locus vcg. It was found that 90% of all clinical isolates possessed the vcgC sequence variant, while 93% of all environmental isolates possessed the vcgE sequence variant. Here we report that the clinical genotype of Vibrio vulnificus is significantly better able to survive in human serum than is the environmental genotype. The presence of a siderophore-encoding gene, viuB, influenced serum survivability among all isolates of V. vulnificus tested. Those strains positive for viuB (all C-type strains but very few E-type strains) showed greater serum survivability than those lacking viuB (most E-type strains). The addition of iron (in the form of ferric ammonium citrate) to human serum restored the survival of E-type strains lacking viuB to levels not significantly different from those of C-type and E-type strains that possess viuB. These findings suggest that viuB may dictate serum survival in both C-and E-type strains of V. vulnificus and may explain why some strains (C-and E-type strains) are pathogenic and others (predominately E-type strains) are not. Additionally, C-type strains exhibited a cross-protective response against human serum, not exhibited by E-type strains, after incubation under nutrient and osmotic downshift conditions that mimicked estuarine waters. This suggests that the nutrient/osmotic environment may influence the survival of V. vulnificus following entry into the human body, leading to selection of the C genotype over the E genotype.Vibrio vulnificus is a gram-negative estuarine bacterium capable of causing fatal septicemia after ingestion of raw or undercooked seafood and infection of wounds following exposure to water containing this pathogen (14, 15). Primary septicemias result in mortality rates exceeding 50%, increasing to more than 90% for patients in shock, despite aggressive treatment (8, 9). Most patients suffering from septicemia have predisposing factors which result in elevated serum iron levels (liver dysfunction, alcohol-induced cirrhosis, hemochromatosis, and thalassemia major) or immunodeficiency (1,2,4,8,14,15,22,23). The FDA estimates that between 12 and 30 million Americans are susceptible to infection, although only ca. 30 cases are reported yearly (14,15).While most clinical and environmental isolates of V. vulnificus possess several virulence factors, few environmental isolates appear capable of human pathogenesis. Virulent isolates of V. vulnificus are generally characterized as encapsulated, resistant to human serum, and able to utilize iron-saturated transferrin. Conversely, avirulent isolates lack one or more of these attributes. However, previous serum studies have indicated that all encapsulated strains, whether of clinical or of environmental origin, were to some extent resistant to human serum, while virulence varied drastically with 50% lethal dose (LD 50 ) values ranging from 1.5 ϫ 10 0 to 7.0 ϫ 10 5 cells (10). Even so, of those strains with LD 50 v...

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Role of Iron in Human Serum Resistance of the Clinical and Environmental Vibrio vulnificus Genotypes

Bogard

Oliver

2007

Appl Environ Microbiol

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“…Apart from siderophore-mediated iron uptake, V. vulnificus utilizes non-transferrin-bound iron through a heme receptor, HupA (92). It has been suggested that non-transferrin-bound iron is required for initiation of V. vulnificus growth; therefore, HupA may be necessary for initial growth once the organism enters the host (60,92).…”

Section: Iron Acquisitionmentioning

confidence: 99%

Vibrio vulnificus: Disease and Pathogenesis

2009

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Vibrio vulnificus is an opportunistic human pathogen that is highly lethal and is responsible for the overwhelming majority of reported seafood-related deaths in the United States (30,117). This bacterium is a part of the natural flora of coastal marine environments worldwide and has been isolated from water, sediments, and a variety of seafood, including shrimp, fish, oysters, and clams (4,7,25,26,43,97,109,116,118,149,165). Consumption of seafood (primarily raw oysters) containing V. vulnificus can result in a severe, fulminant systemic infection. Characteristics of this disease include fever, chills, nausea, hypotensive septic shock, and the formation of secondary lesions on the extremities of patients (11,22,41,74,115,146). This primary septicemia is the most lethal infection caused by V. vulnificus, with an average mortality rate exceeding 50% (30, 41). A review of 459 U.S. cases reported by the FDA between 1992 and 2007 (J. D. Oliver, unpublished) revealed that 51.6% of the patients died. Interestingly, 85.6% of the cases were male; this aspect of the infection is discussed later in this review. Of 180 cases in 2002 to 2007 for which FDA data were available, 92.8% of patients had consumed raw oysters prior to the onset of symptoms and 95.3% had some preexisting disease(s). The latter are clearly associated with V. vulnificus infection, with liver diseases, such as cirrhosis or hepatitis, being the most common (116). In addition to septicemia, V. vulnificus can produce serious wound infections that typically result from exposure of open wounds to water harboring the bacterium (114). Wound infections are frequently contracted as a result of recreational swimming, fishing injuries, or seafood handling (7, 46). Like systemic disease, wound infections progress rapidly to cellulitis, ecchymoses, and bullae, which can progress to necrotizing fasciitis at the site of infection; however, the mortality rate for wound infections (ca. 25%) is lower than that for systemic disease (10,13,74). This organism possesses a wide array of virulence factors, including acid neutralization, capsular polysaccharide expression, iron acquisition, cytotoxicity, motility, and expression of proteins involved in attachment and adhesion. These factors likely require concerted expression for pathogenesis to take place and appear to be under the control of global regulators. Overall, V. vulnificus is a complex microorganism with physiological characteristics that contribute to its survival in the marine environment and in the human host.

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“…More recently, Kim et al (23) showed the involvement of two nonribosomal peptide synthetases in the biosynthesis of vulnibactin. V. vulnificus can grow in human serum only with transferrin at high iron saturation (6); however, Kim et al (22) showed that nontransferrin-bound iron is required for the initiation of V. vulnificus growth. It is customary to use iron-overloaded mice in virulence studies with V. vulnificus to mimic the conditions found in susceptible individuals.…”

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Global Gene Expression as a Function of the Iron Status of the Bacterial Cell: Influence of Differentially Expressed Genes in the Virulence of the Human Pathogen Vibrio vulnificus

2008

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Vibrio vulnificus multiplies rapidly in host tissues under iron-overloaded conditions. To understand the effects of iron in the physiology of this pathogen, we performed a genome-wide transcriptional analysis of V. vulnificus growing at three different iron concentrations, i.e., iron-limiting [Trypticase soy broth with 1.5% NaCl (TSBS) plus ethylenediamine-di-(o-hydroxyphenylacetic) acid (EDDA)], low-iron (1 g Fe/ml; TSBS), and iron-rich (38 g Fe/ml; TSBS plus ferric ammonium citrate) concentrations. A few genes were upregulated under the last two conditions, while several genes were expressed differentially under only one of them. A gene upregulated under both conditions encodes the outer membrane porin, OmpH, while others are related to the biosynthesis of amino sugars. An ompH mutant showed sensitivity to sodium dodecyl sulfate (SDS) and polymyxin B and also had a reduced competitive index compared with the wild type in the iron-overloaded mice. Under iron-limiting conditions, two of the TonB systems involved in vulnibactin transport were induced. These genes were essential for virulence in the iron-overloaded mice inoculated subcutaneously, underscoring the importance of active iron transport in infection, even under the high-iron conditions of this animal model. Furthermore, we demonstrated that a RyhB homologue is also essential for virulence in the iron-overloaded mouse. This novel information on the role of genes induced under iron limitation in the iron-overloaded mouse model and the finding of new genes with putative roles in virulence that are expressed only under iron-rich conditions shed light on the many strategies used by this pathogen to multiply rapidly in the susceptible host.Vibrio vulnificus is an opportunistic marine pathogen that can cause a fatal septicemic disease in humans and eels (17,43). This estuarine bacterium preferentially affects individuals with underlying hepatic diseases and other compromised conditions, such as hemochromatosis and beta thalassemia. In humans, this pathogen frequently causes fatal primary septicemia with a very rapid progress, resulting in a mortality rate of Ͼ50% within a few days (17). The common theme in susceptible individuals appears to be high serum iron levels; however, changes in the innate immune response in the host cannot be discarded (17,19).Iron is an important element in almost all known organisms. In many bacterial pathogens, the ability to acquire this metal from the host is an important virulence factor (7). Seminal work in Oliver's laboratory showed the importance of iron in V. vulnificus infections (74), as the laboratory identified two siderophores, vulnibactin and a hydroxamate-type siderophore, both involved in iron acquisition (59). 70) studied the role of the siderophore vulnibactin in the uptake of iron from transferrin and hemoglobin and identified genes involved in vulnibactin biosynthesis and transport as well as the heme receptor and Fur, a regulator that represses several genes under iron-limiting conditions (13). More recently, K...

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Ferrophilic Characteristics ofVibrio vulnificusand Potential Usefulness of Iron Chelation Therapy

Cited by 38 publications

References 39 publications

Role of Iron in Human Serum Resistance of the Clinical and Environmental Vibrio vulnificus Genotypes

Role of Iron in Human Serum Resistance of the Clinical and Environmental Vibrio vulnificus Genotypes

Vibrio vulnificus: Disease and Pathogenesis

Global Gene Expression as a Function of the Iron Status of the Bacterial Cell: Influence of Differentially Expressed Genes in the Virulence of the Human Pathogen Vibrio vulnificus

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