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Background
Vibrio vulnificus, a gram-negative estuarine bacterium causing severe infectious diseases in humans worldwide [1-4], is the most invasive Vibrio species. Strains of V. vulnificus are divided into 3 biotypes, biotype 1, biotype 2 and biotype 3, by their biochemical properties, host ranges and epidemiological traits [5, 6]. In humans, this pathogen may cause fulminant septicemia with a high mortality rate and wound infections that can be as severe as necrotizing fasciitis, particularly in those with liver cirrhosis and hepatoma. Infection is usually acquired via ingestion of contaminated seafood, mostly raw oysters, or exposure of wounds to seawater/contaminated substances ([7, 8] for reviews).
Both the host factors, Iron-overloaded and immunocompromised conditions [9, 10], and bacterial virulence determinants contribute to the outcome of infection. Clinical V. vulnificus strains produce acidic capsular polysaccharides that prevent the bacterium from killing by complements and phagocytes. They also can acquire iron from the host via producing vulnibactin, a catechol-type siderophore that scavenges iron from various iron sources, and receptors for a variety of iron-containing substances. These properties have been demonstrated to be essential for the virulence of V. vulnificus in the mouse, which is a popular animal model for this pathogen [11-14]. This microorganism produces a few extracellular products, including the metalloprotease Vvp [15], cytolysin VvhA [16] and phospholipase Vpl [17]. A mutant deficient in Vvp, VvhA and Vpl is as virulent as the wild-type strain in the mouse (our unpublished data), indicating that they are all dispensable for virulence. The multifunctional autoprocessing repeats-in-toxin (MARTX), a cytotoxin secreted upon bacterium-cell interaction, is an important virulence factor required for bacterial survival during infection by protecting the organism from phagocytosis [18]. This toxin can also promote bacteria dissemination by causing intestinal tissue damage and inflammation [19]. Other virulence factors that have been studied include flagellum, pili, outer membrane protein OmpU, membrane-bound lipoprotein IlpA, and lysine decarboxylase. Nevertheless, except for the capsule, none of the above-mentioned factors has been shown to result in over 200-fold reduction in virulence if not produced.
We fortuitously isolated a spontaneous mutant that showed greatly reduced virulence in the mouse. In this study, the responsible mutation was mapped to the gene encoding an Lrp family member. We demonstrate that this global regulator controls, directly or indirectly, the expression...