title: Bacterial inhibition of phosphatidylcholine synthesis triggers apoptosis in the brain.
abstract: 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.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: Zweigner
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.forename: Shannon H
authors.initials: SH
authors.lastname: Smith
authors.forename: Marie
authors.initials: M
authors.lastname: Van Der Merwe
authors.forename: Joerg R
authors.initials: JR
authors.lastname: Weber
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003566:Cytidine Diphosphate Choline / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018697:Nootropic Agents / Q000378:metabolism; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D011008:Pneumococcal Infections / Q000378:metabolism; D051381:Rats; D013296:Streptococcus pneumoniae / Q000378:metabolism*
chemical_list: D008244:Lysophosphatidylcholines; D018697:Nootropic Agents; D010713:Phosphatidylcholines; D003566:Cytidine Diphosphate Choline