Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis
Johann S. Braun, … , Elaine I. Tuomanen, Joerg R. Weber
Johann S. Braun, … , Elaine I. Tuomanen, Joerg R. Weber
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):19-27. https://doi.org/10.1172/JCI12035.
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Article

Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis

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.

Authors

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

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Pneumolysin and H2O2 contribute to neuronal damage in the rabbit model o...
Pneumolysin and H2O2 contribute to neuronal damage in the rabbit model of pneumococcal meningitis. (a) Neurotoxicity in the dentate gyrus was quantified by neuronal loss or cell shrinkage assessed in H&E-stained sections. Bars represent means + SD of five brain sections per rabbit. Compared with control animals challenged with PBS, wild-type pneumococci D39 induced significant neurotoxicity (*P < 0.05). Damage in D39-challenged animals was also statistically significant compared with all other tested groups except D39 + NAC (P < 0.05; ANOVA, Student-Newman-Keuls test). #Significant difference between plnA–/spxB– and plnA–, P = 0.04. ##Significant difference between plnA–/spxB– with and without catalase, P = 0.004; t test. (b) Immunohistochemical staining with anti-pneumolysin antibody followed by peroxidase-conjugated secondary antibody and diaminobenzidine (dark color) detected pneumolysin in dentate gyrus neurons of D39- but not plnA–- or PBS-treated animals. Bar = 10 μm.