The Journal of Experimental Medicine
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Published 6 July 2004. doi:10.1084/jem.20032100
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 99-106
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Bacterial Inhibition of Phosphatidylcholine Synthesis Triggers Apoptosis in the Brain

Janine Zweigner1, Suzanne Jackowski1, Shannon H. Smith1, Marie van der Merwe1, Joerg R. Weber2, and Elaine I. Tuomanen1

1 Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105
2 Department of Neurology, Charité-Universitaetsmedizin Berlin, D-10117 Berlin, Germany

Address correspondence to Elaine I. Tuomanen, Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: (901) 495-3114; Fax: (901) 495-3099; email: elaine.tuomanen{at}stjude.org

Streptococcus pneumoniae is the most common cause of bacterial meningitis of high mortality and morbidity. Neurological sequelae include paralysis, mental retardation, and learning disorders. In humans, neurons of the hippocampus undergo apoptosis as a result of meningitis. Phosphatidylcholine (PtdCho) is an essential component of mammalian cell membranes and PtdCho deficiency, either due to chemicals or altered nutrition, leads to apoptosis, especially in hippocampal neurons. We show that apoptosis of a variety of brain cells after pneumococcal infection arises from inhibition of PtdCho biosynthesis, the first such activity described for a bacterium. Apoptosis inhibitors did not prevent the bacterial-dependent inhibition of PtdCho biosynthesis. Supplementation with exogenous lyso-phosphatidylcholine prevents cell death and treatment of mice with cytidine diphosphocholine attenuates hippocampal damage during meningitis, even after the onset of infection. We conclude that bacterial inhibition of PtdCho biosynthesis activates an apoptotic cascade that is a causative event in pathogenesis and amenable to therapeutic intervention.

Key Words: meningitis • Streptococcus pneumoniae • lyso-phosphatidylcholine • CDP-choline • pneumolysin

J. Zweigner's present address is Institute for Microbiology and Hygiene, Charité-Universitaetsmedizin Berlin, Schumannstrasse 20/21, D-10117 Berlin, Germany.

Abbreviations used in this paper: AIF, apoptosis-inducing factor; ALLN, N-acetyl-Leu-Leu-Nle-CHO; CCT, CTP:phosphocholine cytidylyltransferase; CDP-choline, cytidine diphosphocholine; CPT, choline phosphotransferase; LDH, lactate dehydrogenase; lyso-PC, lyso-phosphatidylcholine; PtdCho, phosphatidylcholine.


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