Elsevier

Neurobiology of Disease

Volume 11, Issue 3, December 2002, Pages 355-368
Neurobiology of Disease

Regular Article
Neurotoxicity of Pneumolysin, a Major Pneumococcal Virulence Factor, Involves Calcium Influx and Depends on Activation of p38 Mitogen-Activated Protein Kinase

https://doi.org/10.1006/nbdi.2002.0561Get rights and content

Abstract

Neuronal injury in bacterial meningitis is caused by the interplay of host inflammatory responses and direct bacterial toxicity. We investigated the mechanisms by which pneumolysin, a cytosolic pneumococcal protein, induces damage to neurons. The toxicity after exposure of human SH-SY5Y neuroblastoma cells and hippocampal organotypic cultures to pneumolysin was time- and dose-dependent. Pneumolysin led to a strong calcium influx apparently mediated by pores on the cell membrane formed by the toxin itself and not by voltage-gated calcium channels. Buffering of intracellular calcium with BAPTA-AM [1, 2-bis (o-aminophenoxy) ethane N, N, N′, N′-tetraacetic acid tetra(acetomethoxyl) ester] improved survival of neuronal cells following challenge with pneumolysin. Western blotting revealed increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) as early as 30 min after challenge with pneumolysin. SB 203580, a potent and selective inhibitor of p38 MAPK, rescued human neuronal cells from pneumolysin-induced death. Inhibition of the mitochondrial permeability transition pore using bongkrekate and caspase inhibition also improved survival following challenge with the toxin. Modulation of cell death pathways activated by pneumolysin may influence the outcome of pneumococcal meningitis.

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    Part of these data has been presented as a poster at the 54th Annual Meeting of the American Academy of Neurology in Denver Colorado.

    2

    These authors contributed equally to this work.

    3

    To whom correspondence should be addressed to Dr. Roland Nau, Department of Neurology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. Fax: ++49 551 398405. E-mail: [email protected].

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