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| Item Type: | Preprint |
|---|---|
| Title: | Bradykinin contributes to vasogenic edema in murine experimental cerebral malaria |
| Creators: |
Pinheiro, Alessandro de Sa  ORCID: https://orcid.org/0009-0003-2384-8733, Teixeira, Douglas E., Silva-Aguiar, Rodrigo P. ORCID: https://orcid.org/0000-0003-1975-8033, Shim, Young Jun, Merkulova, Alona, Silbak, Sadiq ORCID: https://orcid.org/0000-0002-4042-2828, Skomorovska-Prokvolit, Yelenna, Midem, David, Ogolla, Sidney ORCID: https://orcid.org/0000-0003-1570-6164, Burckhardt, Bjoern B. ORCID: https://orcid.org/0000-0002-1782-9937, Gangnus, Tanja ORCID: https://orcid.org/0009-0005-7573-6631, Scharfstein, Julio ORCID: https://orcid.org/0000-0002-7510-7625, Caruso-Neves, Celso ORCID: https://orcid.org/0000-0002-2415-7753, McCarty, Owen J.T. ORCID: https://orcid.org/0000-0001-9481-0124, Gailani, David ORCID: https://orcid.org/0000-0001-8142-8014, Bader, Michael ORCID: https://orcid.org/0000-0003-4780-4164, Rosenthal, Phillip, Dent, Arlene E. ORCID: https://orcid.org/0000-0003-2265-7938, Janse, Chris J. ORCID: https://orcid.org/0000-0002-6410-6205, McCrae, Keith ORCID: https://orcid.org/0000-0001-7340-475X, Acacia de Sa Pinheiro, Ana, Kazura, James W. ORCID: https://orcid.org/0000-0002-6390-634X and Schmaier, Alvin H. ORCID: https://orcid.org/0000-0002-3884-6234
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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 (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. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.02.23.704410 |
| Date: | 26 February 2026 |
| Official Publication: | https://doi.org/10.64898/2026.02.23.704410 |
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