The transferrin-iron import system from pathogenic Neisseria species

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Molecular Microbiology (Impact Factor: 4.42). 09/2012; 86(2):246-57. DOI: 10.1111/mmi.12002
Source: PubMed


Two pathogenic species within the genus Neisseria cause the diseases gonorrhoea and meningitis. While vaccines are available to protect against four N. meningitidis serogroups, there is currently no commercial vaccine to protect against serogroup B or against N. gonorrhoeae. Moreover, the available vaccines have significant limitations and with antibiotic resistance becoming an alarming issue, the search for effective vaccine targets to elicit long-lasting protection against Neisseria species is becoming more urgent. One strategy for vaccine development has targeted the neisserial iron import systems. Without iron, the Neisseriae cannot survive and, therefore, these iron import systems tend to be relatively well conserved and are promising vaccine targets, having the potential to offer broad protection against both gonococcal and meningococcal infections. These efforts have been boosted by recent reports of the crystal structures of the neisserial receptor proteins TbpA and TbpB, each solved in complex with human transferrin, an iron binding protein normally responsible for delivering iron to human cells. Here, we review the recent structural reports and put them into perspective with available functional studies in order to derive the mechanism(s) for how the pathogenic Neisseriae are able to hijack human iron transport systems for their own survival and pathogenesis.

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    • "Pseudomonas iron uptake strategies to take-up iron directly from transferrin, this is not an option for P. aeruginosa (Cornelissen, 2003; Noinaj et al., 2012). P. aeruginosa can use different strategies to acquire iron: – Via the production of extracellular Fe 3+ chelating molecules termed siderophores (pyoverdine and pyochelin) and the uptake of ferrisiderophores via TonB-dependent receptors (TBDR). "
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    ABSTRACT: Pseudomonas aeruginosa is a Gram-negative γ-Proteobacterium which is known for its capacity to colonize various niches, including some invertebrate and vertebrate hosts, making it one of the most frequent bacteria causing opportunistic infections. P. aeruginosa is able to cause acute as well as chronic infections and it uses different colonization and virulence factors to do so. Infections range from septicemia, urinary infections, burn wound colonization, and chronic colonization of the lungs of cystic fibrosis patients. Like the vast majority of organisms, P. aeruginosa needs iron to sustain growth. P. aeruginosa utilizes different strategies to take up iron, depending on the type of infection it causes. Two siderophores are produced by this bacterium, pyoverdine and pyochelin, characterized by high and low affinities for iron respectively. P. aeruginosa is also able to utilize different siderophores from other microorganisms (siderophore piracy). It can also take up heme from hemoproteins via two different systems. Under microaerobic or anaerobic conditions, P. aeruginosa is also able to take up ferrous iron via its Feo system using redox-cycling phenazines. Depending on the type of infection, P. aeruginosa can therefore adapt by switching from one iron uptake system to another as we will describe in this short review.
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    • "antibiotic-resistant gonococci (Lewis, 2010), combined with an increase in gonococcal infections, indicating a need for alternative treatment and prevention strategies targeting this organism (Chisholm et al., 2013; Noinaj et al., 2012a). Here, an analysis of the diversity of the hapto-haemoglobin receptor HpuAB in a collection of Neisseria isolates was used to assess the potential of the receptor as a vaccine candidate. "
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    ABSTRACT: A new generation of vaccines containing multiple protein components that aim to provide broad protection against serogroup B meningococci has been developed. One candidate, 4CMenB, has been approved by the European Medicines Agency, but is predicted to provide at most 70-80% strain coverage; hence there is a need for second-generation vaccines that achieve higher levels of coverage. Prior knowledge of the diversity of potential protein vaccine components is a key step in vaccine design. A number of iron import systems have been targeted in meningococcal vaccine development, including the HmbR and Hpu outer membrane proteins, which mediate the utilisation of haemoglobin or haemoglobin-haptoglobin complexes as iron sources. While the genetic diversity of HmbR has been described, little is known of the diversity of Hpu. Using whole genome sequences deposited in a Bacterial Isolate Genome Sequence database (BIGSDB), the prevalence and diversity of Hpu among Neisseria was investigated. Hpu was widely present in a range of Neisseria species whereas HmbR was mainly limited to the pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae. Patterns of sequence variation in sequences from HpuAB proteins were suggestive of recombination and diversifying selection consistent with strong immune selection. Hpu was subject to repeat-mediated phase variation in pathogenic Neisseria and the closely related non-pathogenic Neisseria species Neisseria lactamica and Neisseria polysaccharea but not in the majority of other commensal Neisseria species. These findings are consistent with Hpu being subject to frequent genetic transfer potentially limiting the efficacy of this receptor as a vaccine candidate.
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    ABSTRACT: Exogenous inorganic pyrophosphate increases the biomass yield of Escherichia coli. In this report, we show that the effect of pyrophosphate is related to iron uptake. We have found that addition of pyrophosphate, ammonium iron (III) citrate or iron (III) chloride, in M63 minimal medium containing 1.7 microM of iron, causes an increase in growth yield. In contrast to iron chloride or ammonium iron (III) citrate, exogenous pyrophosphate is deleterious to strains unable to synthesize enterobactin. Thus the positive effect of pyrophosphate is related to the enterobactin uptake system expressed in a low iron content medium. Pyrophosphate in minimal medium has a repressing effect on the expression of Fur-regulated genes. In iron rich medium where enterobactin synthesis is strongly decreased, addition of pyrophosphate increases expression of Fur-regulated genes. Furthermore, this latter regulatory effect of pyrophosphate in iron-rich medium is enhanced in the absence of enterobactin synthesis. It has also been shown that addition of pyrophosphate protects the cell against the oxidative stress caused by the presence of hydrogen peroxide in an iron-rich containing medium. These results indicate that pyrophosphate acts as an iron-chelating agent, could trigger the enterobactin-dependent iron uptake system and could promote an increased binding of iron to enterobactin.
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