Construction and immunological characterization of a novel nontoxic protective pneumolysin mutant for use in future pneumococcal vaccines

Lea-Ann S Kirkham, Alison R Kerr, Gill R Douce, Gavin K Paterson, Deborah A Dilts, Dai-Fang Liu, Tim J Mitchell

Research output: Contribution to journalArticlepeer-review

Abstract

Pneumolysin, the pore-forming toxin produced by Streptococcus pneumoniae, may have an application as an immunogenic carrier protein in future pneumococcal conjugate vaccines. Most of the 90 S. pneumoniae serotypes identified produce pneumolysin; therefore, this protein may confer non-serotype-specific protection against pneumococcal infections such as pneumonia, meningitis, and otitis media. However, as pneumolysin is highly toxic, a nontoxic form of pneumolysin would be a more desirable starting point in terms of vaccine production. Previous pneumolysin mutants have reduced activity but retain residual toxicity. We have found a single amino acid deletion that blocks pore formation, resulting in a form of pneumolysin that is unable to form large oligomeric ring structures. This mutant is nontoxic at concentrations greater than 1,000 times that of the native toxin. We have demonstrated that this mutant is as immunogenic as native pneumolysin without the associated effects such as production of the inflammatory mediators interleukin-6 and cytokine-induced neutrophil chemoattractant KC, damage to lung integrity, and hypothermia in mice. Vaccination with this mutant protects mice from challenge with S. pneumoniae. Incorporation of this mutant pneumolysin into current pneumococcal vaccines may increase their efficacy.

Original languageEnglish
Pages (from-to)586-93
Number of pages8
JournalInfection and Immunity
Volume74
Issue number1
Early online date20 Dec 2005
DOIs
Publication statusE-pub ahead of print - 20 Dec 2005

Keywords

  • Animals
  • Bacterial Proteins/genetics
  • Female
  • Hypothermia
  • Inflammation/metabolism
  • Lung/metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mutagenesis, Site-Directed
  • Pneumococcal Infections/immunology
  • Pneumococcal Vaccines/genetics
  • Streptolysins/genetics

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