Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria

Cerebral malaria (CM) due to Plasmodium falciparum (Pf) infection is a major cause of death in African children. Bradykinin (BK) is a mediator of vasogenic edema. It could contribute to the pathogenesis of central nervous system malaria in Kenyan children and P. berghei ANKA (PbA) infected C57BL/6J mice with experimental cerebral malaria. Cleaved plasma high molecular weight kininogen (cHK) is a marker for prior BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA-infected mice had circulating plasma cHK, elevated BK levels, and reduced HK and prekallikrein levels. HK null (Kng1(-/-)), combined BK B1 and B2 receptor null (Bdkrb1(-/-) / Bdkrb2(-/-)), BK B2 (Bdkrb2(-/-)) or BK B1 (Bdkrb1(-/-)) receptor null mice were protected from neurologic deterioration and brain edema compared to wild-type mice. F12(-/-)mice were not protected from neurological deterioration. Prekallikrein null (Klkb1(-/-)), prolylcarboxypeptidase hypomorphs (Prcp(gt/gt)), and brain endothelial cell conditional knockout of PRCP (Prcp(fl/fl) Cre) mice had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment of PbA-infected mice reversed neurologic deterioration and brain edema and prolonged survival relative to artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.