Dataset Information

The Neisseria gonorrhoeae Methionine Sulfoxide Reductase (MsrA/B) Is a Surface Exposed, Immunogenic, Vaccine Candidate.

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.

SUBMITTER: Jen FE

PROVIDER: S-EPMC6372556 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Neisseria gonorrhoeae Methionine Sulfoxide Reductase (MsrA/B) Is a Surface Exposed, Immunogenic, Vaccine Candidate.

Jen Freda E-C FE Semchenko Evgeny A EA Day Christopher J CJ Seib Kate L KL Jennings Michael P MP

Frontiers in immunology 20190206

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 func ...[more]

PMID: 30787927

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Project description:Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span.

Dataset Information

The Neisseria gonorrhoeae Methionine Sulfoxide Reductase (MsrA/B) Is a Surface Exposed, Immunogenic, Vaccine Candidate.

Publications

The <i>Neisseria gonorrhoeae</i> Methionine Sulfoxide Reductase (MsrA/B) Is a Surface Exposed, Immunogenic, Vaccine Candidate.

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