Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria

Sarah Potter, Tailoi Chan-Ling, Helen J. Ball, Hussein Mansour, Andrew Mitchell, Linda Maluish, Nicholas H. Hunt*

*Corresponding author for this work

Research output: Contribution to journalArticle

95 Citations (Scopus)

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 5 p.i. and became moribund on day 6 p.i. This pathology was not seen in PbA-infected, perforin-deficient (pfp-/-) mice. From days 5-6 p.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 6 p.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 6 p.i. compared with uninfected animals. At day 6 p.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.

Original languageEnglish
Pages (from-to)485-496
Number of pages12
JournalInternational Journal for Parasitology
Volume36
Issue number4
DOIs
Publication statusPublished - Apr 2006
Externally publishedYes

Keywords

  • T lymphocytes
  • cerebral malaria
  • endothelial cells
  • neuroimmunology
  • apoptosis
  • perforin

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