Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase

Research output: Contribution to journalArticlepeer-review

Authors

  • Argyrios K Stringaris
  • Jens Geisenhainer
  • Friederike Bergmann
  • Christoph Balshüsemann
  • Unaa Lee
  • Gregor Zysk
  • Bernhard U Keller
  • Ulrich Kuhnt
  • Joachim Gerber
  • Annette Spreer
  • Mathias Bähr
  • Uwe Michel
  • Roland Nau

Colleges, School and Institutes

Abstract

Neuronal injury in bacterial meningitis is caused by the interplay of host inflammatory responses and direct bacterial toxicity. We investigated the mechanisms by which pneumolysin, a cytosolic pneumococcal protein, induces damage to neurons. The toxicity after exposure of human SH-SY5Y neuroblastoma cells and hippocampal organotypic cultures to pneumolysin was time- and dose-dependent. Pneumolysin led to a strong calcium influx apparently mediated by pores on the cell membrane formed by the toxin itself and not by voltage-gated calcium channels. Buffering of intracellular calcium with BAPTA-AM [1, 2-bis (o-aminophenoxy) ethane N, N, N', N'-tetraacetic acid tetra(acetomethoxyl) ester] improved survival of neuronal cells following challenge with pneumolysin. Western blotting revealed increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) as early as 30 min after challenge with pneumolysin. SB 203580, a potent and selective inhibitor of p38 MAPK, rescued human neuronal cells from pneumolysin-induced death. Inhibition of the mitochondrial permeability transition pore using bongkrekate and caspase inhibition also improved survival following challenge with the toxin. Modulation of cell death pathways activated by pneumolysin may influence the outcome of pneumococcal meningitis.

Details

Original languageEnglish
Pages (from-to)355-68
Number of pages14
JournalNeurobiology of Disease
Volume11
Issue number3
Publication statusPublished - Dec 2002

Keywords

  • Animals, Bacterial Proteins, Blotting, Western, Calcium, Cell Culture Techniques, Cell Survival, Dose-Response Relationship, Drug, Enzyme Inhibitors, Hippocampus, Humans, Imidazoles, Meningitis, Pneumococcal, Mice, Mitochondria, Mitogen-Activated Protein Kinases, Neuroblastoma, Neurons, Organ Culture Techniques, Phosphorylation, Pyridines, Streptolysins, Time Factors, p38 Mitogen-Activated Protein Kinases