Pneumococcal pneumolysin and H₂O₂ mediate brain cell apoptosis during meningitis

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.