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

Abstract

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 ...

Vibrio vulnificus: Disease and Pathogenesis

“…The primary system used by this organism involves siderophores, of which V. vulnificus produces two types: a catechol and a hydroxymate (141). The catechol siderophore (vulnibactin) is the chief means by which V. vulnificus acquires iron and is required for growth in iron-limited media (1,61). Mutational analysis of genes involved in vulnibactin synthesis and transport has demonstrated that this siderophore is also required for scavenging iron from transferrin and holotransferrin (61,157).…”

“…The catechol siderophore (vulnibactin) is the chief means by which V. vulnificus acquires iron and is required for growth in iron-limited media (1,61). Mutational analysis of genes involved in vulnibactin synthesis and transport has demonstrated that this siderophore is also required for scavenging iron from transferrin and holotransferrin (61,157). The suspected role of vulnibactin in virulence was confirmed through mutation of several vulnibactin-associated genes (vuuA, venB, vvsA, and vvsB), which resulted in diminished virulence compared to wild-type strains (64,94,157).…”

Transcriptome profiling analysis of Vibrio vulnificus during human infection

“…These genes encode proteins involved in iron acquisition systems. V. vulnificus utilizes vulnibactin (catechol sidephore) as its main pathway for iron acquisition (Alice et al, 2008;Kim et al, 2006). Previous work that applied mutational gene experiments showed that mutation of vuuA resulted in reduced virulence compared with a wildtype strain (Webster & Litwin, 2000).…”

Host-Nonspecific Iron Acquisition Systems and Virulence in the Zoonotic Serovar of Vibrio vulnificus

“…Bt1 strains use vulnibactin for scavenging iron from human transferrin (Tf) both in vitro and in vivo (in mice, the animal model for human vibriosis). Thus, Bt1 mutants deficient in vulnibactin production or in the vulnibactin receptor (VuuA) grow less efficiently in iron-deficient media and are attenuated in mouse virulence (25)(26)(27). In addition, V. vulnificus Bt1 can utilize non-Tf-bound iron through a heme receptor, HupA, also involved in virulence for mice (28,29).…”