Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis

Johann S. Braun, Jack E. Sublett, Dorette Freyer, Tim J. Mitchell, John L. Cleveland, Elaine I. Tuomanen, Joerg R. Weber

Research output: Contribution to journalArticlepeer-review

262 Citations (Scopus)

Abstract

Pneumococcus is the most common and aggressive cause of bacterial meningitis and induces a novel apoptosis-inducing factor-dependent (AIF-dependent) form of brain cell apoptosis. Loss of production of two pneumococcal toxins, pneumolysin and H2O2, eliminated mitochondrial damage and apoptosis. Purified pneumolysin or H2O2 induced microglial and neuronal apoptosis in vitro. Both toxins induced increases of intracellular Ca2+ and triggered the release of AIF from mitochondria. Chelating Ca2+ effectively blocked AIF release and cell death. In experimental pneumococcal meningitis, pneumolysin colocalized with apoptotic neurons of the hippocampus, and infection with pneumococci unable to produce pneumolysin and H2O2 significantly reduced damage. Two bacterial toxins, pneumolysin and, to a lesser extent, H2O2, induce apoptosis by translocation of AIF, suggesting new neuroprotective strategies for pneumococcal meningitis.

Original languageEnglish
Pages (from-to)19-27
Number of pages9
JournalJournal of Clinical Investigation
Volume109
Issue number1
DOIs
Publication statusPublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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