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Phage proteins are expressed on the surface of Neisseria gonorrhoeae and are potential vaccine candidates.

ABSTRACT: All Neisseria gonorrhoeae strains whose DNA sequences have been determined possess filamentous phage sequences representing their full genomes. The presence of filamentous phage DNA sequences in all sequenced N. gonorrhoeae strains suggest that purified phage particles might be used as a gonococcal vaccine. To test this hypothesis, we purified filamentous Ngo?fil phages and immunized rabbits subcutaneously. The elicited sera contained large quantities of anti-phage IgG and IgA antibodies that bound to the surface of N. gonorrhoeae cells, as shown by ELISA and flow cytometry. The elicited sera bound to the structural Ngo?6fil proteins present in phage particles and to N. gonorrhoeae cells. The sera did not react with gonococcal outer membrane proteins. The sera also had bactericidal activity and blocked adhesion of gonococci to tissue culture cells. These data demonstrate that Ngo?fil phage particles can induce antibodies with anti-gonococcal activity and may be a candidate for vaccine development.

SUBMITTER: Klyz A

PROVIDER: S-EPMC6107182 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Phage proteins are expressed on the surface of Neisseria gonorrhoeae and are potential vaccine candidates.

Kłyż Aneta A Piekarowicz Andrzej A

PloS one 20180823 8

All Neisseria gonorrhoeae strains whose DNA sequences have been determined possess filamentous phage sequences representing their full genomes. The presence of filamentous phage DNA sequences in all sequenced N. gonorrhoeae strains suggest that purified phage particles might be used as a gonococcal vaccine. To test this hypothesis, we purified filamentous NgoΦfil phages and immunized rabbits subcutaneously. The elicited sera contained large quantities of anti-phage IgG and IgA antibodies that bo ...[more]

PMID: 30138416

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Project description:A protective vaccine is the only viable way to stop the spread of gonorrhea in the face of rising antibiotic resistance. However, the notorious phase and antigenic variation of Neisseria gonorrhoeae surface proteins remains one of the challenges in vaccine development. To facilitate vaccine advancement efforts, we carried out comprehensive bioinformatic analyses of sequence variation by comparing 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates deposited in the Neisseria PubMLST database. Eight protein antigens showed exceptional conservation by having a single allele variant distributed in >80% of isolates. An additional 18 vaccine candidates were represented by ≤3 alleles in >50% of N. gonorrhoeae isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between N. gonorrhoeae and N. meningitidis Up to 44% of N. meningitidis alleles for both antigens have premature stop codons, suggesting differential expression. Mapping polymorphisms to the available three-dimensional structures of 12 antigens revealed low-frequency surface polymorphisms. PorB and TbpB possessed numerous high-prevalence polymorphic sites. While TbpA was also highly variable, conserved loops were nonetheless identified. A high degree of sequence conservation, the distribution of a single antigen variant among N. gonorrhoeae strains globally, or low-frequency sequence polymorphisms in surface loops make ACP, AniA, BamA, BamE, MtrE, NspA, NGO0778, NGO1251, NGO1985, OpcA, PldA, Slam2, and ZnuD promising candidates for a gonorrhea vaccine. Finally, the commonly used N. gonorrhoeae FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants.IMPORTANCENeisseria gonorrhoeae, the Gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. N. gonorrhoeae's "superbug" status, its high morbidity, and the serious health impact associated with gonorrhea highlight the importance of vaccine development. One of the longstanding barriers to developing an effective vaccine against N. gonorrhoeae is the remarkable variability of surface-exposed antigens. In this report, we addressed this roadblock by applying extensive bioinformatic analyses to 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates. Our studies are important, as they reveal promising, conserved gonorrhea vaccine candidates and aid structural vaccinology. Moreover, these approaches are broadly applicable to other infectious diseases where surface antigen variability impedes successful vaccine design.

Project description:The sexually transmitted disease gonorrhea (causative agent: Neisseria gonorrhoeae) remains an urgent public health threat globally because of its reproductive health repercussions, high incidence, widespread antimicrobial resistance (AMR), and absence of a vaccine. To mine gonorrhea antigens and enhance our understanding of gonococcal AMR at the proteome level, we performed the first large-scale proteomic profiling of a diverse panel (n = 15) of gonococcal strains, including the 2016 World Health Organization (WHO) reference strains. These strains show all existing AMR profiles - established through phenotypic characterization and reference genome publication - and are intended for quality assurance in laboratory investigations. Herein, these isolates were subjected to subcellular fractionation and labeling with tandem mass tags coupled to mass spectrometry and multi-combinatorial bioinformatics. Our analyses detected 904 and 723 common proteins in cell envelope and cytoplasmic subproteomes, respectively. We identified nine novel gonorrhea vaccine candidates. Expression and conservation of new and previously selected antigens were investigated. In addition, established gonococcal AMR determinants were evaluated for the first time using quantitative proteomics. Six new proteins, WHO_F_00238, WHO_F_00635c, WHO_F_00745, WHO_F_01139, WHO_F_01144c, and WHO_F_01126, were differentially expressed in all strains, suggesting that they represent global proteomic AMR markers, indicate a predisposition toward developing or compensating gonococcal AMR, and/or act as new antimicrobial targets. Finally, phenotypic clustering based on the isolates' defined antibiograms and common differentially expressed proteins yielded seven matching clusters between established and proteome-derived AMR signatures. Together, our investigations provide a reference proteomics data bank for gonococcal vaccine and AMR research endeavors, which enables microbiological, clinical, or epidemiological projects and enhances the utility of the WHO reference strains.

Dataset Information

Phage proteins are expressed on the surface of Neisseria gonorrhoeae and are potential vaccine candidates.

Publications

Phage proteins are expressed on the surface of Neisseria gonorrhoeae and are potential vaccine candidates.

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