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Discovery of Immunodominant B Cell Epitopes within Surface Pneumococcal Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease.

ABSTRACT: The identification of immunodominant B cell epitopes within surface pneumococcal virulence proteins in pediatric patients with invasive pneumococcal disease (IPD) is a valuable approach to define novel vaccine candidates. To this aim, we evaluated sera from children with IPD and age-matched controls against 141 20-mer synthetic peptides covering the entire sequence of major antigenic fragments within pneumococcal virulence proteins; namely, choline-binding protein D (CbpD), pneumococcal histidine triad proteins (PhtD and PhtE), pneumococcal surface protein A (PspA), plasminogen and fibronectin binding protein B (PfbB), and zinc metalloproteinase B (ZmpB). Ten immunodominant B cell epitopes were identified: CbpD-pep4 (amino acids (aa) 291-310), PhtD-pep11 (aa 88-107), PhtD-pep17 (aa 172-191), PhtD-pep19 (aa 200-219), PhtE-pep32 (aa 300-319), PhtE-pep40 (aa 79-98), PfbB-pep76 (aa 180-199), PfbB-pep79 (aa 222-241), PfbB-pep90 (aa 484-503), and ZmpB-pep125 (aa 431-450). All epitopes were highly conserved among different pneumococcal serotypes, and four of them were located within the functional zinc-binding domain of the histidine triad proteins PhtD and PhtE. Peptides CbpD-pep4, PhtD-pep19, and PhtE-pep40 were broadly recognized by IPD patient sera with prevalences of 96.4%, 92.9%, and 71.4%, respectively, whereas control sera exhibited only minor reactivities (<10.7%). Their specificities for IPD were 93.3%, 95%, and 96.7%; their sensitivities were 96.4%, 92.9%, and 71.4% and their positivity likelihood ratios for IPD were 14.5, 18.6, and 21.4, respectively. Furthermore, purified antibodies against CbpD-pep4, PhtD-pep19, and PhtE-pep40 readily bound on the surfaces of different pneumococcal serotypes, as assessed by FACS and immunofluorescence analysis. The identified immunodominant B cell epitopes provide a better understanding of immune response in IPD and are worth evaluation in additional studies as potential vaccine candidates.

SUBMITTER: Lagousi T

PROVIDER: S-EPMC4646002 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Discovery of Immunodominant B Cell Epitopes within Surface Pneumococcal Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease.

Lagousi Theano T Routsias John J Piperi Christina C Tsakris Athanassios A Chrousos George G Theodoridou Maria M Spoulou Vana V

The Journal of biological chemistry 20150922 46

The identification of immunodominant B cell epitopes within surface pneumococcal virulence proteins in pediatric patients with invasive pneumococcal disease (IPD) is a valuable approach to define novel vaccine candidates. To this aim, we evaluated sera from children with IPD and age-matched controls against 141 20-mer synthetic peptides covering the entire sequence of major antigenic fragments within pneumococcal virulence proteins; namely, choline-binding protein D (CbpD), pneumococcal histidin ...[more]

PMID: 26396191

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Project description:Streptococcus pneumoniae remains the leading causative pathogen in pediatric pneumonia and bacteremia throughout the world. The invasive pneumococcal disease (IPD) is known as isolation of S. pneumoniae from a normally sterile site (e.g., blood, cerebrospinal fluid, synovial fluid, pericardial fluid, pleural fluid, or peritoneal fluid). The aim of this study is to survey the clinical manifestations and laboratory results of IPD and identify the prognostic factors of mortality. From January 2001 to December 2006, a retrospective review of chart was performed in a teaching hospital in Taipei. The hospitalized pediatric patients with the diagnosis of pneumonia, arthritis, infectious endocarditis, meningitis or sepsis were recruited. Among them, 50 patients were pneumococcal infections proved by positive culture results or antigen tests. Clinical manifestations, laboratory data and hospitalization courses were analyzed. The median age was 3.5-year-old and there were 30 male patients (60%). Eight patients (16%) had underlying disease such as leukemia or congenital heart disease. Hemolytic uremic syndrome (HUS) was observed in ten patients and extracorporeal membrane oxygenation (ECMO) was performed in three patients. Leukocytosis, elevated C-reactive protein and AST level were noted in most of the patients. The overall mortality rate was 10%. We found that leukopenia, thrombocytopenia and high CRP level were significant predictors for mortality. In conclusion, S. pneumoniae remains an important health threat worldwide and IPD is life-threatening with high mortality rate. We found leukopenia, thrombocytopenia, and high CRP levels to be associated with mortality in pediatric IPD, and these factors are worthy of special attention at admission. Although we failed to identify a statistically significant prognostic factor in multivariate analysis due to relatively small sample size, we suggest an aggressive antibiotic treatment in patients with these factors at admission. Further large-scale studies are warranted.

Project description:The opportunistic pathogen Staphylococcus aureus has become a major threat for human health and well-being by developing resistance to antibiotics, and by its fast evolution into new lineages that rapidly spread within the healthy human population. This calls for the development of active or passive immunization strategies to prevent or treat acute phase infections. Since no such anti-staphylococcal immunization approaches are available as yet, the present studies were aimed at identifying new leads for their development. For this purpose, we thoroughly profiled the cell surface-exposed staphylococcal proteome by combining two surface shaving approaches. In parallel, non-covalently cell wall-bound proteins were extracted with KSCN and analyzed by gel-free proteomics, and also the exoproteome was analyzed through gel-free proteomics. Lastly, we screened a selection of the identified cell wall-attached proteins for binding of immunoglobulin G from patients that have been challenged with different types of S. aureus over extended periods of time due to chronic wound colonization. The combined results of these analyses highlight particular cell surface-exposed S. aureus proteins with highly immunogenic epitopes as potentially powerful targets for the development of protective anti-staphylococcal immunization strategies. Bioinformatics pipeline: Reduction and alkylation, desalting of the samples, mass spectrometric (MS) analysis and database searches were performed as previously described (PMID: 20662103). The strain-specific uniprot databases were used for the /S. aureus/ strains Newman and USA300, respectively including concatenated reversed databases with 5250 and 5298 entries. Validation of MS/MS-based peptide and protein identifications was performed with Scaffold (version Scaffold_2_04_00, Proteome Software Inc., Portland, OR). Peptide identifications were accepted if they exceeded the specific database search engine thresholds. Sequest identifications required at least deltaCn scores of greater than 0.10 and XCorr scores of greater than 1.9, 2.2, 3.8 and 3.8 for singly, doubly, triply and quadruply charged peptides, respectively. All experiments were conducted in independent triplicates. Peptides were only accepted as identified if they were detected in at least two out of the three replicates per sample set. With these filter parameters no false positive hits were obtained.

Dataset Information

Discovery of Immunodominant B Cell Epitopes within Surface Pneumococcal Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease.

Publications

Discovery of Immunodominant B Cell Epitopes within Surface Pneumococcal Virulence Proteins in Pediatric Patients with Invasive Pneumococcal Disease.

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