Protein I, a translocatable ion channel from Neisseria gonorrhoeae, selectively inhibits exocytosis from human neutrophils without inhibiting O2- generation.

Haines, KA; Yeh, Li-An; Blake, M. S.; Cristello, Paul; Korchak, Helen M.; Weissmann, Gerald

doi:10.1016/s0021-9258(19)35444-4

Cited by 62 publications

(13 citation statements)

References 42 publications

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“…In the past decade, there has been much speculation about additional biological functions of porins, particularly in bacterial pathogenesis. For the neisserial P.I porins, these speculations were largely based on observations that P.I proteins spontaneously translocate as functional voltage-gated ion channels into planar lipid bilayers and plasma membranes of eukaryotic cells (36,40,44), and impair neutrophil function by causing a transient change in membrane potential and interference with cell signaling events (41)(42)(43). By a mechanism seemingly unrelated to its channel forming activity (61), the neisserial P.I proteins also exhibit mitogenic potential and stimulate immunoglobulin secretion by lymphocytes, in line with their strong efficacy as adjuvants (62,63).…”

Section: Discussionmentioning

confidence: 99%

“…Purified P.I also inserts into plasma membranes of eukaryotic cells. The addition of purified P.I to mammalian cells causes a transient change in transmembrane potential and modulates host cell signaling events (36,(41)(42)(43)(44), but direct evidence for insertion of a functional pore upon infection of mammalian cells with intact microorganisms is not available.…”

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confidence: 99%

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Gonococcal Invasion of Epithelial Cells Driven by P.IA, a Bacterial Ion Channel with GTP Binding Properties

Putten

Duensing

Carlson

1998

The Journal of Experimental Medicine

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The neisserial porin P.I is a GTP binding protein that forms a voltage-gated channel that translocates into mammalian cell membranes and modulates host cell signaling events. Here, we report that P.I confers invasion of the bacterial pathogen Neisseria gonorrhoeae into Chang epithelial cells and that this event is controlled by GTP, as well as other phosphorus-containing compounds. Bacterial invasion was observed only for strains carrying the P.IA subtype of porin, which is typically associated with the development of disseminated neisserial disease, and did not require opacity outer membrane proteins, previously recognized as gonococcal invasins. Allelic replacement studies showed that bacterial invasiveness cotransferred with the P.IA (por1A) gene. Mutation of the P.I-associated protein Rmp did not alter the invasive properties. Cross-linking of labeled GTP to the porin revealed more efficient GTP binding to the P.IA than P.IB porin subtype. GTP binding was inhibited by an excess of unlabeled GTP, ATP, and GDP, as well as inorganic phosphate, but not by UTP or beta-glycerophosphate, fully in line with the respective invasion-inhibitory activities observed for these compounds. The P.IA-mediated cellular invasion may explain the more invasive behavior of P.IA strains in the natural infection and may broaden the basis for the development of a P.I-based gonococcal vaccine.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Gonococcal Invasion of Epithelial Cells Driven by P.IA, a Bacterial Ion Channel with GTP Binding Properties

Putten

Duensing

Carlson

1998

The Journal of Experimental Medicine

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“…In addition, protein I can be transferred from the intact gonococcus into artificial lipid bilayers and human cells (12,40) . When purified protein I is added to a suspension of human neutrophils, it associates with these cells as demonstrated by immunoblotting (30). We have previously demonstrated that treatment of neutrophils with protein I of N. gonorrhoeae inhibits FMLP-induced homotypic cell/cell adhesion of neutrophils, addition of membrane to the cell surface, and exocytosis of granule enzymes (30).…”

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confidence: 99%

“…When purified protein I is added to a suspension of human neutrophils, it associates with these cells as demonstrated by immunoblotting (30). We have previously demonstrated that treatment of neutrophils with protein I of N. gonorrhoeae inhibits FMLP-induced homotypic cell/cell adhesion of neutrophils, addition of membrane to the cell surface, and exocytosis of granule enzymes (30). However, assembly of the multicomponent NADPH oxidase was possible for superoxide anion generation proceeds in an unimpaired fashion as does calcium movements-measured by changes in the fluorescent dye, Fura-2.…”

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confidence: 99%

Effects of protein I of Neisseria gonorrhoeae on neutrophil activation: generation of diacylglycerol from phosphatidylcholine via a specific phospholipase C is associated with exocytosis.

Haines

Reibman

Tang

et al. 1991

The Journal of Cell Biology

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. Upon engagement of chemoattractant receptors, neutrophils generate inositol trisphosphate and diacylglycerol (DG) by means of a phosphatidylinositolspecific phospholipase C (PI-PLC) which is regulated by a GTP-binding protein(s) . We have previously reported (Reibman, J., H. M. Korchak, L. B. Vosshall, K. A. Haines, A. M. Rich, and G. Weissmann. 1988. J. Biol. Chem. 263 :6322-6328) a biphasic rise in DG after exposure of neutrophils to the chemoattractant FMLP: a rapid (<15 s) phase ("triggering") and a slow (>,30 s) phase ("activation") . These derive from distinct intracellular lipid pools. To study the source of rapid and slow DG, we have used a unique probe, protein I, a porin that is the major outer membrane protein of Neisseria gonorrhoeae. Treatment of neutrophils with protein I inhibits exocytosis and homotypic cell adhesion provoked by FMLP without inhibiting assembly of the NADPH oxidase responsible for OZ genera-

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“…The porin PorB (also known as protein I) is one of the most abundant proteins in the gonococcal cell envelope and acts primarily as a voltage-gated channel to facilitate ion exchange with the environment (59). N. gonorrhoeae isolates possess one copy of PorB in one of two allelic forms, PorB.IA or PorB.IB, which share only ;70% nucleotide sequence identity (60).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

Baarda

Zielke

Holm

et al. 2021

mSphere

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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. IMPORTANCE Neisseria 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.

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Protein I, a translocatable ion channel from Neisseria gonorrhoeae, selectively inhibits exocytosis from human neutrophils without inhibiting O2- generation.

Cited by 62 publications

References 42 publications

Gonococcal Invasion of Epithelial Cells Driven by P.IA, a Bacterial Ion Channel with GTP Binding Properties

Gonococcal Invasion of Epithelial Cells Driven by P.IA, a Bacterial Ion Channel with GTP Binding Properties

Effects of protein I of Neisseria gonorrhoeae on neutrophil activation: generation of diacylglycerol from phosphatidylcholine via a specific phospholipase C is associated with exocytosis.

Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

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