CNS cell death in bacterial meningitis

Bacterial infection of the CNS is hazardous not only because of its often-lethal acute effects, but also because it leads to the death of irreplaceable neurons and glia. Braun et al. have established microglial and neuronal cell culture systems in which to study the mechanisms by which Pneumococcus bacteria induce cell death. In a recent paper in the Journal of Infectious Disease, these same authors showed that exposure to these bacteria induces a caspase-independent cell death pathway. In this response, the mitochondrial protein apoptosis-inducing factor (AIF) translocates to the nucleus, where it activates some of the early events in apoptosis, including chromosomal condensation, DNA cleavage, and translocation of phosphatidylserine to the cell surface. Here, Braun et al. show that AIF activation and cell death can be induced by either of two secreted bacterial factors: hydrogen peroxide and the toxic protein pneumolysin, which forms pores in animal cell membranes. The authors inactivated both of these factors, first by using bacterial strains with specific mutations that block their production, and second by adding exogenous inhibitors. Simultaneous inhibition of pneumolysin and peroxide protects the cells from bacteria-induced killing, both in culture and in vivo. Interestingly, however, even when the bacteria fail to produce peroxide, host cells exposed to the bacteria generate it endogenously and are still subject to apoptotic death, albeit with lower efficiency. Most likely, inflammation caused by some additional bacterial factor is responsible for this residual pro-apoptotic effect.

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