Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria

Pinheiro, A. d. S.; Teixeira, D. E.; Silva-Aguiar, R. P.; Shim, Y. J.; Merkulova, A.; Silbak, S.; Skomorovska-Prokvolit, Y.; Midem, D.; Ogolla, S.; Burckhardt, B. B.; Gangnus, T.; Scharfstein, J.; Caruso-Neves, C.; McCarty, O. J.; Gailani, D.; Bader, M.; Rosenthal, P.; Dent, A. E.; Janse, C. J.; McCrae, K.; Pinheiro, A. A. d. S.; Kazura, J. W.; Schmaier, A. H.

doi:10.64898/2026.02.23.704410

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bioRxiv · 10.64898/2026.02.23.704410

Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria

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Abstract

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 (Prcpgt/gt), and brain endothelial cell conditional knockout of PRCP (Prcpfl/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.

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Pinheiro, A. d. S., Teixeira, D. E., Silva-Aguiar, R. P., Shim, Y. J., Merkulova, A., Silbak, S., Skomorovska-Prokvolit, Y., Midem, D., Ogolla, S., Burckhardt, B. B., Gangnus, T., Scharfstein, J., Caruso-Neves, C., McCarty, O. J., Gailani, D., Bader, M., Rosenthal, P., Dent, A. E., Janse, C. J., McCrae, K., Pinheiro, A. A. d. S., Kazura, J. W., Schmaier, A. H.. 2026-02-26. Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria. https://doi.org/10.64898/2026.02.23.704410

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