Analysis of the human Ig isotype response to individual transferrin binding proteins A and B from Neisseria meningitidis

Johnson, Anthea; Gorringe, Andrew; Fox, Andrew; Borrow, Ray; Robinson, A.

doi:10.1111/j.1574-695x.1997.tb01085.x

Cited by 16 publications

(2 citation statements)

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“…that TbpB should be considered as a candidate for a possible vaccine against N. meningitidis infection (1)(2)(3)19). TbpB antibodies can be measured in convalescent-phase sera from patients with meningococcal disease (18,19,22); they are protective in a mouse model of infection, and they are also bactericidal in laboratory animals (24). However, TbpB is highly variable in different strains of N. gonorrhoeae and, taken together with lower tbpB transcript amounts produced in subject samples, may explain why we observed lower titers of IgG antibody against TbpB antigen than against TbpA.…”

Section: Discussionmentioning

confidence: 99%

The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection

et al. 2005

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Iron is limiting in the human host, and bacterial pathogens respond to this environment by regulating gene expression through the ferric uptake regulator protein (Fur). In vitro studies have demonstrated that Neisseria gonorrhoeae controls the expression of several critical genes through an iron-and Fur-mediated mechanism. While most in vitro experiments are designed to determine the response of N. gonorrhoeae to an exogenous iron concentration of zero, these organisms are unlikely to be exposed to such severe limitations of iron in vivo. To determine if N. gonorrhoeae expresses iron-and Fur-regulated genes in vivo during uncomplicated gonococcal infection, we examined gene expression profiles of specimens obtained from male subjects with urethral infections. RNA was isolated from urethral swab specimens and used as a template to amplify, by reverse transcriptase PCR (RT-PCR), gonococcal genes known to be regulated by iron and Fur (tbpA, tbpB, and fur). The constitutively expressed gonococcal rmp gene was used as a positive control. RT-PCR analysis indicated that gonorrhea-positive specimens where rmp expression was seen were also 93% (51/55) fbpA positive, 87% (48/55) tbpA positive, and 86% (14 of 16 tested) tbpB positive. In addition, we detected a fur transcript in 79% (37 of 47 tested) of positive specimens. We also measured increases in levels of immunoglobulin G antibody against TbpA (91%) and TbpB (73%) antigens in sera from infected male subjects compared to those in uninfected controls. A positive trend between tbpA gene expression and TbpA antibody levels in sera indicated a relationship between levels of gene expression and immune response in male subjects infected with gonorrhea for the first time. These results indicate that gonococcal iron-and Fur-regulated tbpA and tbpB genes are expressed in gonococcal infection and that male subjects with mucosal gonococcal infections exhibit antibodies to these proteins.

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Section: Discussionmentioning

confidence: 99%

The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection

et al. 2005

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“…TbpA is currently being considered as a candidate for inclusion in a meningococcal vaccine effective against all serogroups. Recombinant TbpA produces a strong immunogenic response in mice, protecting them from subsequent intraperitoneal challenge with N.meningitidis (West et al, 2001), while antibodies in sera from diseased patients cross-react with a range of meningococcal isolates (Gorringe et al, 1995;Johnson et al, 1997). TbpB displays greater sequence heterogeneity between strains and ranges in molecular weight from 65 to 85 kDa.…”

Section: Introductionmentioning

confidence: 99%

Homology modelling of transferrin-binding protein A from Neisseria meningitidis

Oakhill¹,

Sutton²,

Gorringe³

et al. 2005

Protein Engineering, Design and Selection

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Neisseria meningitidis, a causative agent of bacterial meningitis, obtains transferrin-bound iron by expressing two outer membrane located transferrin-binding proteins, TbpA and TbpB. TbpA is thought to be an integral outer membrane pore that facilitates iron uptake. Evidence suggests that TbpA is a useful antigen for inclusion in a vaccine effective against meningococcal disease, hence the identification of regions involved in ligand binding is of paramount importance to design strategies to block uptake of iron. The protein shares sequence and functional similarities to the Escherichia coli siderophore receptors FepA and FhuA, whose structures have been determined. These receptors are composed of two domains, a 22-stranded beta-barrel and an N-terminal plug region that sits within the barrel and occludes the transmembrane pore. A three-dimensional TbpA model was constructed using FepA and FhuA structural templates, hydrophobicity analysis and homology modelling. TbpA was found to possess a similar architecture to the siderophore receptors. In addition to providing insights into the highly immunogenic nature of TbpA and allowing the prediction of potentially important ligand-binding epitopes, the model also reveals a narrow channel through its entire length. The relevance of this channel and the spatial arrangement of external loops, to the mechanism of iron translocation employed by TbpA is discussed.

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Patterns of structural and sequence variation within isotype lineages of the Neisseria meningitidis transferrin receptor system

et al. 2015

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Neisseria meningitidis inhabits the human upper respiratory tract and is an important cause of sepsis and meningitis. A surface receptor comprised of transferrin-binding proteins A and B (TbpA and TbpB), is responsible for acquiring iron from host transferrin. Sequence and immunological diversity divides TbpBs into two distinct lineages; isotype I and isotype II. Two representative isotype I and II strains, B16B6 and M982, differ in their dependence on TbpB for in vitro growth on exogenous transferrin. The crystal structure of TbpB and a structural model for TbpA from the representative isotype I N. meningitidis strain B16B6 were obtained. The structures were integrated with a comprehensive analysis of the sequence diversity of these proteins to probe for potential functional differences. A distinct isotype I TbpA was identified that co-varied with TbpB and lacked sequence in the region for the loop 3 α-helix that is proposed to be involved in iron removal from transferrin. The tightly associated isotype I TbpBs had a distinct anchor peptide region, a distinct, smaller linker region between the lobes and lacked the large loops in the isotype II C-lobe. Sequences of the intact TbpB, the TbpB N-lobe, the TbpB C-lobe, and TbpA were subjected to phylogenetic analyses. The phylogenetic clustering of TbpA and the TbpB C-lobe were similar with two main branches comprising the isotype 1 and isotype 2 TbpBs, possibly suggesting an association between TbpA and the TbpB C-lobe. The intact TbpB and TbpB N-lobe had 4 main branches, one consisting of the isotype 1 TbpBs. One isotype 2 TbpB cluster appeared to consist of isotype 1 N-lobe sequences and isotype 2 C-lobe sequences, indicating the swapping of N-lobes and C-lobes. Our findings should inform future studies on the interaction between TbpB and TbpA and the process of iron acquisition.

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Analysis of the human Ig isotype response to individual transferrin binding proteins A and B from Neisseria meningitidis

Cited by 16 publications

References 16 publications

The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection

The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection

Homology modelling of transferrin-binding protein A from Neisseria meningitidis

Patterns of structural and sequence variation within isotype lineages of the Neisseria meningitidis transferrin receptor system

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