Cytotoxic T Lymphocyte Granzyme-b mediates neuronal cell death during Plasmodium berghei ANKA induced experimental cerebral malaria

Cerebral malaria is a complex, acute, neurological disease characterised by a sudden onset of cerebral symptoms. This disease is manifested as initial arousable stage that is followed by an unarousable coma and eventually death. Parasite burden and CD8+ T cell count in the brain determines the disease outcome. Cytotoxic CD8+ T cell-derived Granzyme-b is required for the development of experimental cerebral malaria (ECM), but the mechanism of pathogenesis is not known. Here, we show that CD8+ T cells infiltrate in to the brain during ECM releasing Granzyme-b that is cytotoxic to neuronal cells. Granzyme-b kills neuronal cells through direct cytotoxicity and also by activating neuronal caspase-3 and calpain1 via cytoskeletal breakdown. Our results showed the increased expression of cell adhesion molecules and chemokine receptors in the brain and their associated infiltration of T cells during ECM.