Role of the Gonococcal Neisserial Heparin Binding Antigen in Microcolony Formation, and Serum Resistance and Adherence to Epithelial Cells

Semchenko, Evgeny A.; Mubaiwa, Tsitsi D.; Day, Christopher J.; Seib, Kate L.

doi:10.1093/infdis/jiz628

Cited by 13 publications

(12 citation statements)

References 40 publications

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“…This is above the estimated infectious dose for gonococcal infection (e.g., ID50 of the male urethra~2.3 × 10 3 CFU [38]), which suggests that vaccine-induced antibodies could reduce the level of initial host colonization by N. gonorrhoeae. NHBA interacts with several glycans [26] and antibodies to the full length NHBA, but not NHBA-c, and were able to block interactions with heparin. In N. meningitidis the central arginine-rich region of NHBA is required for heparin binding [16], and antibodies to the arginine-rich region of the full length gonococcal NHBA may be responsible for reduced heparin binding.…”

Section: Discussionmentioning

confidence: 97%

“…We have also shown that NHBA Ng binds to several glycans including heparin (K D , 4.4 nM) and chondroitin sulfate (K D , 73 nM), and is involved in interactions with both gonococcal and host cells [26]. Furthermore, a gonococcal nhba mutant has decreased cell aggregation and microcolony formation, and reduced survival in human serum and reduced adherence to human cervical and urethral epithelial cells, relative to the wild type strain [26]. However, the exact nature of gonococcal NHBA-mediated interactions with the host has not been determined and the host receptor(s) involved in adherence are unknown.…”

Section: Introductionmentioning

confidence: 94%

“…Similarly, a 1:20 dilution of NHBA-c antisera reduces bacterial adherence 8-and 5-fold in tCX and tUEC cells, respectively (Figure 5b). Gonococcal NHBA is involved in adherence to human cervical and urethral epithelial cells [26], therefore, we investigated whether NHBA and NHBA-c antisera can reduce adherence. In vitro infection assays were performed with transformed cervical (tCX) and urethral (tUEC) epithelial cells with N. gonorrhoeae that was pre-incubated with antisera.…”

Section: Nhba Antibodies Reduce Nhba Binding To Heparin and Gonococcmentioning

confidence: 99%

“…We recently showed that NHBA Ng is surface exposed and is recognized by antibodies from people vaccinated with 4CMenB [12]. We have also shown that NHBA Ng binds to several glycans including heparin (K D , 4.4 nM) and chondroitin sulfate (K D , 73 nM), and is involved in interactions with both gonococcal and host cells [26]. Furthermore, a gonococcal nhba mutant has decreased cell aggregation and microcolony formation, and reduced survival in human serum and reduced adherence to human cervical and urethral epithelial cells, relative to the wild type strain [26].…”

Section: Introductionmentioning

confidence: 99%

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The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells

2020

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Due to the continuing emergence of multidrug resistant strains of Neisseria gonorrhoeae there is an urgent need for the development of a gonococcal vaccine. We evaluated the gonococcal Neisseria heparin binding antigen (NHBA) as a potential vaccine candidate, in terms of its sequence conservation and expression in a range of N. gonorrhoeae strains, as well as its immunogenicity and the functional activity of antibodies raised to either the full length NHBA or a C-terminal fragment of NHBA (NHBA-c). The gene encoding NHBA is highly conserved and expressed in all N. gonorrhoeae strains investigated. Recombinant NHBA is immunogenic, and mice immunized with either NHBA or NHBA-c adjuvanted with either Freund’s or aluminium hydroxide (alum) generated a humoral immune response, with predominantly IgG1 antibodies. Antibodies generated by both NHBA and NHBA-c antigens promoted complement activation and mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity, with slightly higher titers seen for the NHBA-c antigen. Anti-NHBA was also able to block the functional activity of NHBA by reducing binding to heparin and adherence to cervical and urethral epithelial cells. These data suggest that the gonococcal NHBA is a promising vaccine antigen to include in a vaccine to control N. gonorrhoeae.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 94%

Section: Nhba Antibodies Reduce Nhba Binding To Heparin and Gonococcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells

2020

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“…Using mass spectrometry and genetic deletion mutants, we identified several cross-reactive Ng proteins, including MtrE, PilQ, BamA, PorB, and NHBA, the gonococcal homolog of one of the recombinant components of 4CMenB. All of these proteins show promise as gonococcal vaccine targets [18,64].…”

Section: Plos Pathogensmentioning

confidence: 99%

The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

et al. 2020

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There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development.

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Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

Lewis

Ram

2020

FEBS Letters

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Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, while Neisseria meningitidis is an important cause of bacterial meningitis and sepsis. Complement is a central arm of innate immune defenses and plays an important role in combating Neisserial infections. Persons with congenital and acquired defects in complement are at a significantly higher risk for invasive Neisserial infections such as invasive meningococcal disease and disseminated gonococcal infection compared to the general population. Of note, Neisseria gonorrhoeae and Neisseria meningitidis can only infect humans, which in part may be related to their ability to evade only human complement. This review summarizes the epidemiologic and clinical aspects of Neisserial infections in persons with defects in the complement system. Mechanisms used by these pathogens to subvert killing by complement and preclinical studies showing how these complement evasion strategies may be used to counteract the global threat of meningococcal and gonococcal infections are discussed.

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Role of the Gonococcal Neisserial Heparin Binding Antigen in Microcolony Formation, and Serum Resistance and Adherence to Epithelial Cells

Cited by 13 publications

References 40 publications

The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells

The Neisseria gonorrhoeae Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells

The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae

Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

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