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Bacterial inhibition of phosphatidylcholine synthesis induces apoptosis in brain cells

Abstract number: 902_p1050

Zweigner J.

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Objectives:

Streptococcus pneumoniae is the most common cause of bacterial meningitis of high mortality and morbidity. In humans, neurons of the hippocampus undergo apoptosis as a result of meningitis. Phosphatidylcholine (PtdCho) is an essential component of mammalian cell membranes and phosphatidylcholine deficiency, either due to chemicals or altered nutrition, leads to apoptosis, especially in hippocampal neurons.

Methods:

Microglia, neurons, and brain endothelial cells were infected with 107/mL pneumococcal strain D39 capsular type 2, its unencapsulated derivate R6, the pneumolysin-negative mutant plan-, the pyruvate oxidase mutant spxB-, or the plan-/spxB double mutant for 4 h. Translocation of phosphatidylserine and decrease of mitochondrial transmembrane potential as measurements of apoptosis were detected by FACS analysis. Synthesis of PtdCho was measured by incorporation of [methyl-3H]choline. Inhibition of apoptosis in vivo was demonstrated by pretreatment of infected C57BL/6 mice with citicoline. Damage in the hippocampus was quanitified by Tunel staining.

Results:

D39 and R6 significantly inhibited phosphatidylcholine biosynthesis (41.2 ± 6 and 67.4 ± 8%, respectively) causing apoptosis of several different types brain cells. Loss of H2O2 or/and pneumolysin significantly reduced the ability of pneumocci to cause cell death and caused less inhibition of PtdCho synthesis, with [methyl-3H]choline incorporation into PtdCho increasing to 57.8, 77.9, 92.4%, respectively, compared with uninfected control cells. Supplementation with exogenous lysophosphatidylcholine prevented cell death in vitro and treatment of mice with CDP-choline attenuated hippocampal damage during meningitis. Apoptosis inhibitors ZVAD, ALLN, fumonisin B1 or BAPTA-AM did not prevent the bacterial-dependent inhibition of phosphatidylcholine biosynthesis.

Conclusions:

We conclude that bacterial inhibition of phosphatidylcholine biosynthesis activates an apoptotic cascade that is a causative event in pathogenesis and is amenable to therapeutic intervention.

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Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Subject:
Location: Oxford, UK
Presentation type:
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