Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis.
Pneumococcus is the most common and aggressive cause of bacterial meningitis and induces a novel apoptosis-inducing factor-dependent (AIF-dependent) form of brain cell apoptosis. Loss of production of two pneumococcal toxins, pneumolysin and H(2)O(2), eliminated mitochondrial damage and apoptosis. Purified pneumolysin or H(2)O(2) induced microglial and neuronal apoptosis in vitro. Both toxins induced increases of intracellular Ca(2+) and triggered the release of AIF from mitochondria. Chelating Ca(2+) effectively blocked AIF release and cell death. In experimental pneumococcal meningitis, pneumolysin colocalized with apoptotic neurons of the hippocampus, and infection with pneumococci unable to produce pneumolysin and H(2)O(2) significantly reduced damage. Two bacterial toxins, pneumolysin and, to a lesser extent, H(2)O(2), induce apoptosis by translocation of AIF, suggesting new neuroprotective strategies for pneumococcal meningitis.
Braun
Johann S
JS
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Sublett
Jack E
JE
Freyer
Dorette
D
Mitchell
Tim J
TJ
Cleveland
John L
JL
Tuomanen
Elaine I
EI
Weber
Joerg R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051033:Apoptosis Inducing Factor; D001426:Bacterial Proteins; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D005420:Flavoproteins / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008565:Membrane Proteins / Q000096:biosynthesis; D008586:Meningitis, Pneumococcal / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D008959:Models, Neurological; D051381:Rats; D013296:Streptococcus pneumoniae / Q000472:pathogenicity; D013301:Streptolysins / Q000633:toxicity*
C494829:AIFM1 protein, human; C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D001426:Bacterial Proteins; D005420:Flavoproteins; D008565:Membrane Proteins; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D006861:Hydrogen Peroxide