Gonococcal transferrin binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice

Price, Gregory A.; Masri, Heather P.; Hollander, Aimee M.; Russell, Michael W.; Cornelissen, Cynthia Nau

doi:10.1016/j.vaccine.2007.07.038

Cited by 55 publications

(45 citation statements)

References 50 publications

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“…Generation of iron-dependent growth curves. Growth curves were generated using the following protocol, modified from one described previously (54). Gonococcal strains were plated from freezer stocks onto GCB plates containing Kellogg's supplement 1 and 12 M ferric nitrate.…”

Section: Methodsmentioning

confidence: 99%

ThefbpABCOperon Is Required for Ton-Independent Utilization of Xenosiderophores byNeisseria gonorrhoeaeStrain FA19

2011

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Neisseria gonorrhoeae produces no known siderophores but can employ host-derived, iron-binding proteins, including transferrin and lactoferrin, as iron sources. Given the propensity of this pathogen to hijack rather than synthesize iron-sequestering molecules, we hypothesized that the ability to use siderophores produced by other bacteria, or xenosiderophores, may also play a role in the survival of the gonococcus. Among a panel of diverse siderophores, only the catecholate xenosiderophores enterobactin and salmochelin promoted growth of gonococcal strain FA19. Surprisingly, the internalization pathway was independent of TonB or any of the TonB-dependent transporters. Xenosiderophore-mediated growth was similarly independent of the pilinextruding secretin formed by PilQ and of the hydrophobic-agent efflux system composed of MtrCDE. The fbpABC operon encodes a periplasmic-binding-protein-dependent ABC transport system that enables the gonococcus to transport iron into the cell subsequent to outer membrane translocation. We hypothesized that the FbpABC proteins, required for ferric iron transport from transferrin and lactoferrin, might also contribute to the utilization of xenosiderophores as iron sources. We created mutants that conditionally expressed FbpABC from an IPTG-inducible promoter. We determined that expression of FbpABC was required for growth of gonococcal strain FA19 in the presence of enterobactin and salmochelin. The monomeric component of enterobactin, dihydroxybenzoylserine (DHBS), and the S2 form of salmochelin specifically promoted FbpABC-dependent growth of FA19. This study demonstrated that the gonococcal FbpABC transport system is required for utilization of some xenosiderophores as iron sources and that growth promotion by these ferric siderophores can occur in the absence of TonB or individual TonB-dependent transporters.

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Section: Methodsmentioning

confidence: 99%

ThefbpABCOperon Is Required for Ton-Independent Utilization of Xenosiderophores byNeisseria gonorrhoeaeStrain FA19

2011

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“…Some of these proteins have been wellcharacterized, including iron acquisition transporters such as the transferrin receptor system composed of TbpA and TbpB, ferric enterobactin receptor FetA and periplasmic iron-binding transporter FetB, ferric binding protein A (FbpA), TonB-dependent transporter TdfG, and ExbB (62)(63)(64)(65)(66). The TbpA and TbpB proteins are being pursued as gonorrhea vaccine candidates because of their conservation within specific regions among different isolates, importance in N. gonorrhoeae pathophysiology, and abilities to elicit cross-reactive and bactericidal antibodies (48,67).…”

Section: Effect Of Iron Deprivation On the Cell Envelope Proteinmentioning

confidence: 99%

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

Zielke

Wierzbicki

Baarda

et al. 2016

Molecular & Cellular Proteomics

178

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Expanding efforts to develop preventive gonorrhea vaccines is critical because of the dire possibility of untreatable gonococcal infections. Reverse vaccinology, which includes genome and proteome mining, has proven very successful in the discovery of vaccine candidates against many pathogenic bacteria. However, progress with this approach for a gonorrhea vaccine remains in its infancy. Accordingly, we applied a comprehensive proteomic platform-isobaric tagging for absolute quantification coupled with two-dimensional liquid chromatography and mass spectrometry-to identify potential gonococcal vaccine antigens. Our previous analyses focused on cell envelopes and naturally released membrane vesicles derived from four different Neisseria gonorrhoeae strains. Here, we extended these studies to identify cell envelope proteins of N. gonorrhoeae that are ubiquitously expressed and specifically induced by physiologically relevant environmental stimuli: oxygen availability, iron deprivation, and the presence of human serum. Together, these studies enabled the identification of numerous potential gonorrhea vaccine targets. Initial characterization of five novel vaccine candidate antigens that were ubiquitously expressed under these different growth conditions demonstrated that homologs of BamA (NGO1801), LptD (NGO1715), and TamA (NGO1956), and two uncharacterized proteins, NGO2054 and NGO2139, were surface exposed, secreted via naturally released membrane vesicles, and elicited bactericidal antibodies that cross-reacted with a panel of temporally and geographically diverse isolates. In addition, analysis of polymorphisms at the nucleotide and amino acid levels showed that these vaccine candidates are highly conserved among N. gonorrhoeae strains. Finally, depletion of BamA caused a loss of N. gonorrhoeae viability, suggesting it may be an essential target. Together, our data strongly support the use of proteomics-driven discovery of potential vaccine targets as a sound approach for identifying promising gonococcal antigens. Molecular & Cellular

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“…The present results coupled with our previous findings (16) suggest that the targeting of the antigen (SBR) to APC by recombinant coupling to CTA2/B is important in the induction of responses to SBR. This represents one strategy for exploiting the immunoenhancing properties of heat-labile enterotoxins to create mucosal vaccines, while avoiding the toxicity inherent in the A1 subunits (10,(38)(39)(40)(41)(42). The present findings reveal one mechanism by which these constructs work to enhance mucosal immune responses, by promoting the uptake of the coupled antigen into mucosal DC, the CCR7-mediated migration of antigen-containing DC into the MLN, and interaction of the DC with predominantly Th1 and Th17 cells.…”

Section: Discussionmentioning

confidence: 67%

Identification and Characterization of Intestinal Antigen-Presenting Cells Involved in Uptake and Processing of a Nontoxic Recombinant Chimeric Mucosal Immunogen Based on Cholera Toxin Using Imaging Flow Cytometry

Zhao

Minderman

Russell

2013

Clin. Vaccine Immunol.

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Gonococcal transferrin binding protein chimeras induce bactericidal and growth inhibitory antibodies in mice

Cited by 55 publications

References 50 publications

ThefbpABCOperon Is Required for Ton-Independent Utilization of Xenosiderophores byNeisseria gonorrhoeaeStrain FA19

ThefbpABCOperon Is Required for Ton-Independent Utilization of Xenosiderophores byNeisseria gonorrhoeaeStrain FA19

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

Identification and Characterization of Intestinal Antigen-Presenting Cells Involved in Uptake and Processing of a Nontoxic Recombinant Chimeric Mucosal Immunogen Based on Cholera Toxin Using Imaging Flow Cytometry

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