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Published on: June 8, 2017
Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria
Sarah Potter1, Tailoi Chan-Ling, Helen J Ball
1Department of Pathology, Medical Foundation Building (K25), University of Sydney, Sydney, NSW 2006, Australia.
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.
Insights
Perforin plays a critical role in cerebral malaria pathogenesis. CD8+ T lymphocytes induce endothelial cell apoptosis via a perforin-dependent pathway, contributing to fatal outcomes in murine cerebral malaria.
Area of Science:
- Immunology
- Neuroscience
- Pathology
Background:
- Cerebral malaria (CM) is a severe Plasmodium falciparum complication.
- The exact mechanisms driving CM pathogenesis remain incompletely understood.
- Perforin's role in CM has not been fully elucidated.
Purpose of the Study:
- To investigate the role of perforin in experimental cerebral malaria (ECM) pathogenesis.
- To determine the involvement of CD8+ T cells and endothelial cell apoptosis in ECM.
Main Methods:
- Utilized a murine model of cerebral malaria using Plasmodium berghei ANKA (PbA) infection.
- Compared pathology in wild-type C57BL/6 mice with perforin-deficient (pfp-/-) mice.
- Analyzed gene expression (mRNA for granzyme B, CD8, CD4, perforin) and performed immunohistochemistry for perforin and CD8+ cells.
- Assessed endothelial cell apoptosis using TUNEL and activated caspase-3 staining.
Main Results:
- PbA-infected C57BL/6 mice exhibited typical ECM neuropathology and mortality.
- Perforin-deficient mice did not develop ECM pathology.
- Increased mRNA for granzyme B and CD8, but not CD4, was observed in infected brains.
- Perforin mRNA and protein were significantly upregulated in PbA-infected C57BL/6 mice.
- Elevated CD8+ cell infiltration within cerebral microvessels was noted.
- TUNEL-positive and activated caspase-3 positive endothelial cells were present in ECM, significantly reduced in pfp-/- mice.
Conclusions:
- CD8+ T lymphocytes induce endothelial cell apoptosis through a perforin-dependent mechanism in murine cerebral malaria.
- Perforin is a key mediator in the fatal pathogenic process of experimental cerebral malaria.
- Targeting the perforin pathway may offer therapeutic strategies for cerebral malaria.
