title: Apoptosis-inducing factor mediates microglial and neuronal apoptosis caused by pneumococcus.
abstract: Streptococcus pneumoniae is the major cause of bacterial meningitis and it damages the hippocampus by inducing neuronal apoptosis. The blocking of caspases provides only partial protection in experimental meningitis, which suggests that there is an additional apoptotic pathway. A trigger of this pathway is the bacterium itself, as exposure of microglia or neurons to live pneumococci induces rapid apoptosis. In this study, apoptosis was not associated with the activation of caspases-1-10 and was not inhibited by z-VAD-fmk, a broad-spectrum caspase inhibitor. Rather, apoptosis was attributed to damage to mitochondria, which was followed by the release of apoptosis-inducing factor (AIF) from the mitochondria, large-scale DNA fragmentation, and hypodiploidy. Furthermore, intracytoplasmatic microinjection of AIF-specific antiserum markedly impaired pneumococcus-induced apoptosis. These findings indicate that AIF may play a central role in brain cell apoptosis and bacterial pathogenesis.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, University of Tennessee, Memphis, TN 38105, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Braun
authors.forename: R
authors.initials: R
authors.lastname: Novak
authors.forename: P J
authors.initials: PJ
authors.lastname: Murray
authors.forename: C M
authors.initials: CM
authors.lastname: Eischen
authors.forename: S A
authors.initials: SA
authors.lastname: Susin
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: A
authors.initials: A
authors.lastname: Halle
authors.forename: J R
authors.initials: JR
authors.lastname: Weber
authors.forename: E I
authors.initials: EI
authors.lastname: Tuomanen
authors.forename: J L
authors.initials: JL
authors.lastname: Cleveland
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D001921:Brain; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000473:pathology; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004171:Diploidy; D005420:Flavoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D016920:Meningitis, Bacterial / Q000503:physiopathology; D051379:Mice; D017628:Microglia / Q000382:microbiology / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000382:microbiology / Q000473:pathology*; D011008:Pneumococcal Infections / Q000503:physiopathology; D013296:Streptococcus pneumoniae / Q000502:physiology*
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D004247:DNA