title: Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria.
abstract: Cerebral malaria is a serious complication of Plasmodium falciparum infection. We have investigated the role of perforin in the pathogenesis of cerebral malaria in a murine model (Plasmodium berghei ANKA (PbA) infection). C57BL/6 mice demonstrated the typical neuropathological symptoms of experimental cerebral malaria infection from day 5p.i. and became moribund on day 6p.i. This pathology was not seen in PbA-infected, perforin-deficient (pfp-/-) mice. From days 5-6p.i. onwards there was a significant increase in mRNA for granzyme B and CD8, but not CD4, in brain tissue from PbA-infected C57BL/6 and pfp-/- mouse brains. Perforin mRNA was strongly increased in the brains of PbA-infected C57BL/6 mice on day 6p.i. Immunohistochemistry revealed increased perforin staining and elevated numbers of CD8(+) cells within the cerebral microvessels in PbA-infected C57BL/6 at days 5 and 6p.i. compared with uninfected animals. At day 6p.i., there were TUNEL-positive cells and activated caspase-3 positive cells of endothelial morphology in the CNS of PbA-infected C57BL/6 mice. The TUNEL-positive cells were greatly reduced in pfp-/- mice. These results suggest that CD8(+)T lymphocytes induce apoptosis of endothelial cells via a perforin-dependent process, contributing to the fatal pathogenic process in murine cerebral malaria.
authors.affiliation: Department of Pathology, Medical Foundation Building (K25), University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Potter
authors.forename: Tailoi
authors.initials: T
authors.lastname: Chan-Ling
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.forename: Hussein
authors.initials: H
authors.lastname: Mansour
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchell
authors.forename: Linda
authors.initials: L
authors.lastname: Maluish
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001812:Blood-Brain Barrier / Q000469:parasitology; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology*; D005260:Female; D016779:Malaria, Cerebral / Q000276:immunology / Q000469:parasitology / Q000473:pathology* / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018512:Parasitemia / Q000276:immunology / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin