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Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae.

ABSTRACT: Four previously identified immunodominant B-cell epitopes, located within known virulent pneumococcal proteins CbpD, PhtD, PhtE, and ZmpB, had shown promising in vivo immunological characteristics, indicating their potential to be used as vaccine antigens. In this study, we further evaluated the opsonophagocytic activity of antibodies against these epitopes and their capacity to protect mice from pneumococcal sepsis. An opsonophagocytic killing assay (OPKA) revealed that OPKA titers of human anti-peptide antibodies against pneumococcal serotypes 1, 3, and 19A were significantly higher (P < 0.001) than those of the control sera, suggesting their functional potential against virulent clinical isolates. Data obtained from mice actively immunized with any of the selected epitope analogues or with a mixture of these (G_Mix group) showed, compared to controls, enhanced survival against the highly virulent pneumococcal serotype 3 (P < 0.001). Moreover, passive transfer of hyperimmune serum from G_Mix to naive mice also conferred protection to a lethal challenge with serotype 3, which demonstrates that the observed protection was antibody mediated. All immunized murine groups elicited gradually higher antibody titers and avidity, suggesting a maturation of immune response over time. Among the tested peptides, PhD_pep19 and PhtE_pep40 peptides, which reside within the zinc-binding domains of PhtD and PhtE proteins, exhibited superior immunological characteristics. Recently it has been shown that zinc uptake is of high importance for the virulence of Streptococcus pneumoniae; thus, our findings suggest that these epitopes deserve further evaluation as novel immunoreactive components for the development of a polysaccharide-independent pneumococcal vaccine.

SUBMITTER: Papastamatiou T

PROVIDER: S-EPMC5820952 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae.

Papastamatiou Theodora T Routsias John G JG Koutsoni Olga O Dotsika Eleni E Tsakris Athanassios A Spoulou Vana V

Infection and immunity 20180220 3

Four previously identified immunodominant B-cell epitopes, located within known virulent pneumococcal proteins CbpD, PhtD, PhtE, and ZmpB, had shown promising <i>in vivo</i> immunological characteristics, indicating their potential to be used as vaccine antigens. In this study, we further evaluated the opsonophagocytic activity of antibodies against these epitopes and their capacity to protect mice from pneumococcal sepsis. An opsonophagocytic killing assay (OPKA) revealed that OPKA titers of hu ...[more]

PMID: 29263108

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Project description:During the past decades, with the implementation of pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCVs), a dramatic reduction in vaccine type diseases and transmissions has occurred. However, it is necessary to develop a less expensive, serotype-independent pneumococcal vaccine due to the emergence of nonvaccine-type pneumococcal diseases and the limited effect of vaccines on colonization. As next-generation vaccines, conserved proteins, such as neuraminidase A (NanA), elongation factor Tu (Tuf), and pneumolysin (Ply), are promising targets against pneumococcal infections. Here, we designed and constructed a novel fusion protein, NanAT1-TufT1-PlyD4, using the structural and functional domains of full-length NanA, Tuf and Ply proteins with suitable linkers based on bioinformatics analysis and molecular cloning technology. Then, we tested whether the protein protected against focal and lethal pneumococcal infections and examined its potential protective mechanisms. The fusion protein NanAT1-TufT1-PlyD4 consists of 627 amino acids, which exhibits a relatively high level of thermostability, high stability, solubility and a high antigenic index without allergenicity. The purified fusion protein was used to subcutaneously immunize C57BL/6 mice, and NanAT1-TufT1-PlyD4 induced a strong and significant humoral immune response. The anti-NanAT1-TufT1-PlyD4 specific IgG antibody assays increased after the first immunization and reached the highest value at the 35th day. The results from in vitro experiments showed that anti-NanAT1-TufT1-PlyD4 antisera could inhibit the adhesion of Streptococcus pneumoniae (S. pneumoniae) to A549 cells. In addition, immunization with NanAT1-TufT1-PlyD4 significantly reduced S. pneumoniae colonization in the lung and decreased the damage to the lung tissues induced by S. pneumoniae infection. After challenge with a lethal dose of serotype 3 (NC_WCSUH32403), a better protection effect was observed with NanAT1-TufT1-PlyD4-immunized mice than with the separate full-length proteins and the adjuvant control; the survival rate was 50%, which met the standard of the marketed vaccine. Moreover, we showed that the humoral immune response and the Th1, Th2 and Th17-cellular immune pathways are involved in the immune protection of NanAT1-TufT1-PlyD4 to the host. Collectively, our results support that the novel fusion protein NanAT1-TufT1-PlyD4 exhibits extensive immune stimulation and is effective against pneumococcal challenges, and these properties are partially attributed to humoral and cellular-mediated immune responses.

Dataset Information

Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae.

Publications

Evaluation of Protective Efficacy of Selected Immunodominant B-Cell Epitopes within Virulent Surface Proteins of Streptococcus pneumoniae.

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