Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage

Carolin Wippel, Jana Maurer, Christina Förtsch, Sabrina Hupp, Alexandra Bohl, Jiangtao Ma, Timothy J Mitchell, Stephanie Bunkowski, Wolfgang Brück, Roland Nau, Asparouh I Iliev

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

Original languageEnglish
Pages (from-to)e1003380
JournalPLoS pathogens
Issue number6
Publication statusPublished - 2013


  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Astrocytes
  • Bacterial Proteins
  • Dendrites
  • Dizocilpine Maleate
  • Frontal Lobe
  • Glutamic Acid
  • Humans
  • Meningitis, Pneumococcal
  • Mice
  • Middle Aged
  • Receptors, N-Methyl-D-Aspartate
  • Streptococcus pneumoniae
  • Streptolysins
  • Synapses


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