28 SEPTEMBER 2012 Bacterial Pathogenesis and Iron Uptake Iron is an essential element in a variety of metabolic cellular pathways. Vertebrates sequester iron from invading pathogens as a means of nutritional immunity to deprive pathogens of this key nutritional component. Thus, the bioavailability of iron in the biological fluids of a vertebrate host is extremely limited because it is sequestered by high-affinity iron-binding proteins, such as transferrin in serum and extracellular fluids, lactoferrin on mucosal surfaces, and ovotransferrin in eggs (Payne 1997). Invading bacterial pathogens sense iron depletion as a signal that they are within a host, inducing the expression of iron uptake genes, allowing the pathogen to overcome host defenses. To obtain this host-sequestered iron, most pathogenic bacteria have developed iron uptake systems that usually are mediated by siderophores, organic compounds that sequester iron from host proteins, or direct uptake iron from host protein mediated hemolysins or proteases (Crosa et al. 2004). In Gram-negative bacteria, iron homeostasis is controlled by the ferric uptake regulator (Fur) protein (Bagg and Neilands 1987, Escolar et al. 1997, Hantke 2001). The Fur protein acts as a repressor of transcription (DNA to messenger RNA process) of iron-regulated genes. In the presence of iron, Fur makes a dimer that represses the transcription of specific genes related to iron transport and virulence. Homologues of the fur gene have been described in numerous Gramnegative bacteria, including several pathogens, such as Yersinia (Staggs and Perry 1991), Salmonella (Ernst et al. 1978), Vibrio (Litwin et al. 1992, Litwin and Calderwood 1993, Yamamoto et al. 1997), Pseudomonas (Prince et al. 1993), Helicobacter pylori (Bereswill et al. 1998), Bordetella (Brickman and Armstrong 1995), Campylobacter (Wooldridge et al. 1994), Acinetobacter baumannii (Daniel et al. 1999), Legionella (Hickey and Cianciotto 1994), Neisseria (Berish et al. 1993), Haemophilus (Carson et al. 1996) and even in plant pathogens, such as Erwinia chrysanthemi (Franza et al. 1999). These homologues of fur protein have similar mechanisms to control iron acquisition (Escolar et al. 1999). Iron Acquisition by Edwardsiella ictaluri Channel catfish (Ictalurus punctatus) is the most important aquaculture species in the United States, accounting for more than 60 percent of all U.S. Developing Live Attenuated Vaccines by Deleting Genes for Iron Metabolism in Pathogenic Bacteria Javier Santander 1 FIGURE 2. Virulence of E. ictaluri Dfur in fish hosts. A. Zebrafish i.m. infected with E. ictaluri wild type; B. Zebrafish i.m. infected with E. ictaluri Dfur-35; C. Catfish i.c. infected with E. ictaluri wild type; D. Catfish i.c. infected with E. ictaluri Dfur-35 (Santander et al. in press). FIGURE 1. Phenotype and genotype of Edwardsiella ictaluri Dfur. A. Deletion map of fur gene indicates the 311 bp in frame deleted; B. Genotype verification of E. ictaluri Dfur-35 by PCR; C. Detection of siderophores in CAS indicator agar plates; D. Detection of secreted siderophores in E. ictaluri strains grown under iron-rich (+) and iron-limited (–) conditions by TLC; E. Outer membrane profiles of E. ictaluri strains grown under iron-rich (+Fe (BHI broth), ++Fe (BHI broth +150 mM FeSO4 )) and iron-limited (–Fe) conditions (Santander et al. in press).
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