Structure-guided Antigen Engineering Yields Pneumolysin Mutants Suitable for Vaccination against Pneumococcal Disease

Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-04, Vol.286 (14), p.12133-12140
Main Authors: Oloo, Eliud O., Yethon, Jeremy A., Ochs, Martina M., Carpick, Bruce, Oomen, Raymond
Format: Article
Language:English
Subjects:
Animals
Antigen
Antigens, Bacterial
Bacterial Proteins - adverse effects
Bacterial Proteins - genetics
Bacterial Proteins - immunology
Bacterial Proteins - metabolism
Bacterial Toxins
Calorimetry, Differential Scanning
Cells, Cultured
Cholesterol-dependent Cytolysin
Circular Dichroism
Computer Modeling
Hemolysis - drug effects
Immunology
Membrane Proteins
Molecular Design
Mutagenesis, Site-Directed
Pneumococcal Infections - immunology
Pneumococcal Infections - prevention & control
Pneumococcal Vaccines - immunology
Protein Structure
Protein Structure and Folding
Protein Structure, Secondary
Sheep
Site-directed Mutagenesis
Streptococcus pneumoniae
Streptolysins - adverse effects
Streptolysins - genetics
Streptolysins - immunology
Streptolysins - metabolism
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Summary:Pneumolysin (PLY) is a cholesterol-binding, pore-forming protein toxin. It is an important virulence factor of Streptococcus pneumoniae and a key vaccine target against pneumococcal disease. We report a systematic structure-driven approach that solves a long-standing problem for vaccine development in this field: detoxification of PLY with retention of its antigenic integrity. Using three conformational restraint techniques, we rationally designed variants of PLY that lack hemolytic activity and yet induce neutralizing antibodies against the wild-type toxin. These results represent a key milestone toward a broad-spectrum protein-based pneumococcal vaccine and illustrate the value of structural knowledge in formulating effective strategies for antigen optimization.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.191148