Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking

Research output: Contribution to journalArticlepeer-review


  • Asparouh I Iliev
  • Jasmin Roya Djannatian
  • Felipe Opazo
  • Joachim Gerber
  • Roland Nau
  • Fred S Wouters

Colleges, School and Institutes


Streptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells--neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.


Original languageEnglish
Pages (from-to)461-77
Number of pages17
JournalMolecular Microbiology
Issue number2
Publication statusPublished - Jan 2009


  • Acetylation, Animals, Bacterial Proteins, CHO Cells, Cell Line, Tumor, Cholesterol, Cricetinae, Cricetulus, Humans, Mice, Microtubules, Prefrontal Cortex, Rabbits, Streptococcus pneumoniae, Streptolysins, Tubulin, Virulence Factors, src-Family Kinases