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

Argyrios K. Stringaris; Jens Geisenhainer; Friederike Bergmann; Christoph Balshüsemann; Unaa Lee; Gregor Zysk; Timothy J. Mitchell; Bernhard U. Keller; Ulrich Kuhnt; Joachim Gerber; Annette Spreer; Mathias Bähr; Uwe Michel; Roland Nau

Neurobiology of Disease (Dec 2002)

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

Argyrios K. Stringaris,
Jens Geisenhainer,
Friederike Bergmann,
Christoph Balshüsemann,
Unaa Lee,
Gregor Zysk,
Timothy J. Mitchell,
Bernhard U. Keller,
Ulrich Kuhnt,
Joachim Gerber,
Annette Spreer,
Mathias Bähr,
Uwe Michel,
Roland Nau

Affiliations

Argyrios K. Stringaris: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Jens Geisenhainer: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Friederike Bergmann: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Christoph Balshüsemann: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Unaa Lee: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Gregor Zysk: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Timothy J. Mitchell: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Bernhard U. Keller: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Ulrich Kuhnt: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Joachim Gerber: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Annette Spreer: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Mathias Bähr: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Uwe Michel: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany
Roland Nau: Department of Neurology, University of Göttingen, 37075, Göttingen, Germany; Department of Neurophysiology, University of Göttingen, 37075, Göttingen, Germany; Department of Medical Microbiology and Virology, University of Düsseldorf, 40225, Düsseldorf, Germany; Division of Infection and Immunity, University of Glasgow, Glasgow, Scotland; Max Planck Institute for Biophysical Chemistry, 37075, Göttingen, Germany

Journal volume & issue: Vol. 11, no. 3
pp. 355 – 368

Abstract

Read online

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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords