Abstract
Control of the sexually transmitted infection gonorrhea is a major public health challenge, due to the recent emergence of multidrug resistant strains of Neisseria gonorrhoeae, and there is an urgent need for novel therapies or a vaccine to prevent gonococcal disease. In this study, we evaluated the methionine sulfoxide reductase (MsrA/B) of N. gonorrhoeae as a potential vaccine candidate, in terms of its expression, sequence conservation, localization, immunogenicity, and the functional activity of antibodies raised to it. Gonococcal MsrA/B has previously been shown to reduce methionine sulfoxide [Met(O)] to methionine (Met) in oxidized proteins and protect against oxidative stress. Here we have shown that the gene encoding MsrA/B is present, highly conserved, and expressed in all N. gonorrhoeae strains investigated, and we determined that MsrA/B is surface is exposed on N. gonorrhoeae. Recombinant MsrA/B is immunogenic, and mice immunized with MsrA/B and either aluminum hydroxide gel adjuvant or Freund's adjuvant generated a humoral immune response, with predominantly IgG1 antibodies. Higher titers of IgG2a, IgG2b, and IgG3 were detected in mice immunized with MsrA/B-Freund's adjuvant compared to MsrA/B-aluminum hydroxide adjuvant, while IgM titers were similar for both adjuvants. Antibodies generated by MsrA/B-Freund's in mice mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity. Anti-MsrA/B was also able to functionally block the activity of MsrA/B by inhibiting binding to its substrate, Met(O). We propose that recombinant MsrA/B is a promising vaccine antigen for N. gonorrhoeae.
Highlights
Neisseria gonorrhoeae is an obligate human pathogen that infects human mucosal surfaces and causes the sexually transmitted infection gonorrhea
Analysis of N. gonorrhoeae genome strains in GenBank revealed that MsrA/B is highly conserved, being present in 100% of 468 strains, with 99–100% amino acid identity over the length of the 522 amino acid protein
Targeting bacterial factors important for survival or virulence is a potential strategy for vaccine development, as a protective immune response against N. gonorrhoeae may encompass both functional blocking of human-specific disease processes as well as conventional immune killing processes
Summary
Neisseria gonorrhoeae is an obligate human pathogen that infects human mucosal surfaces and causes the sexually transmitted infection gonorrhea. Symptomatic gonococcal infection typically presents as urethritis in males and cervicitis in females, infection of the rectum, pharynx, and eye occur in both sexes [2]. Gonorrhea can Vaccine Potential of Gonococcal MsrA/B lead to severe sequelae, such as pelvic inflammatory disease, adverse pregnancy outcomes, neonatal complications, and infertility, and can increase the risk of acquiring and transmitting HIV [reviewed in Edwards et al [3]]. The challenges include the lack of protective immunity following infection, and the absence of a correlates of protection, as well as the high level of phase and antigenic variation of N. gonorrhoeae surface antigens [reviewed in Edwards et al [3] and Rice et al [5]]. Vaccine antigens should be conserved, immunogenic, and be able to induce functional antibodies that are able to mediate bactericidal or opsonophagocytic killing, and/or that are able to block an important function of N. gonorrhoeae [reviewed in Edwards et al [3]]
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