Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking

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Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking. / Iliev, Asparouh I; Djannatian, Jasmin Roya; Opazo, Felipe; Gerber, Joachim; Nau, Roland; Mitchell, Timothy J; Wouters, Fred S.

In: Molecular Microbiology, Vol. 71, No. 2, 01.2009, p. 461-77.

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@article{0d169688d11f4706a7b26300686f1134,
title = "Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking",
abstract = "Streptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells--neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.",
keywords = "Acetylation, Animals, Bacterial Proteins, CHO Cells, Cell Line, Tumor, Cholesterol, Cricetinae, Cricetulus, Humans, Mice, Microtubules, Prefrontal Cortex, Rabbits, Streptococcus pneumoniae, Streptolysins, Tubulin, Virulence Factors, src-Family Kinases",
author = "Iliev, {Asparouh I} and Djannatian, {Jasmin Roya} and Felipe Opazo and Joachim Gerber and Roland Nau and Mitchell, {Timothy J} and Wouters, {Fred S}",
year = "2009",
month = jan,
doi = "10.1111/j.1365-2958.2008.06538.x",
language = "English",
volume = "71",
pages = "461--77",
journal = "Molecular Microbiology",
issn = "0950-382X",
publisher = "Wiley",
number = "2",

}

RIS

TY - JOUR

T1 - Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking

AU - Iliev, Asparouh I

AU - Djannatian, Jasmin Roya

AU - Opazo, Felipe

AU - Gerber, Joachim

AU - Nau, Roland

AU - Mitchell, Timothy J

AU - Wouters, Fred S

PY - 2009/1

Y1 - 2009/1

N2 - Streptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells--neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.

AB - Streptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells--neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.

KW - Acetylation

KW - Animals

KW - Bacterial Proteins

KW - CHO Cells

KW - Cell Line, Tumor

KW - Cholesterol

KW - Cricetinae

KW - Cricetulus

KW - Humans

KW - Mice

KW - Microtubules

KW - Prefrontal Cortex

KW - Rabbits

KW - Streptococcus pneumoniae

KW - Streptolysins

KW - Tubulin

KW - Virulence Factors

KW - src-Family Kinases

U2 - 10.1111/j.1365-2958.2008.06538.x

DO - 10.1111/j.1365-2958.2008.06538.x

M3 - Article

C2 - 19040644

VL - 71

SP - 461

EP - 477

JO - Molecular Microbiology

JF - Molecular Microbiology

SN - 0950-382X

IS - 2

ER -