Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria.
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.
Potter
Sarah
S
Department of Pathology, Medical Foundation Building (K25), University of Sydney, Sydney, NSW 2006, Australia.
Chan-Ling
Tailoi
T
Ball
Helen J
HJ
Mansour
Hussein
H
Mitchell
Andrew
A
Maluish
Linda
L
Hunt
Nicholas H
NH
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
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin