Year: 2026
Type: article
Abstract: Cerebral malaria (CM) from Plasmodium falciparum is a major cause of death in African children. Since bradykinin (BK) is a mediator of vasogenic edema, we hypothesized that it contributes to the pathogenesis of CM in Kenyan children and Plasmodium berghei ANKA-infected (PbA-infected) C57BL/6J mice in experimental CM (ECM). Cleaved plasma high-molecular-weight kininogen (cHK) is a marker for 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 with ECM had circulating cHK, elevated BK levels, and reduced HK and prekallikrein activity/antigen levels. HK-null (Kng1-/-), combined BK B1- and B2 receptor-null (Bdkrb1-/-Bdkrb2-/-), BK B2 receptor-null (Bdkrb2-/-), or BK B1 receptor-null (Bdkrb1-/-) mice were protected significantly from neurologic deterioration and brain edema compared with wild-type mice. F12-/- mice were not protected from neurological deterioration. Prekallikrein-null (Klkb1-/-), prolylcarboxypeptidase hypomorph (Prcpgt/gt), and brain endothelial cell conditional KO of PRCP (Prcpfl/fl Cre) mice with ECM had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment in PbA-infected mice reversed neurologic deterioration and brain edema and significantly prolonged survival over artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.
DOI: 10.1172/jci202285
Authors: Alessandro de Sa Pinheiro, Douglas E. Teixeira, Rodrigo P. Silva-Aguiar, Young Jun Shim, Alona A. Merkulova, Sadiq Silbak, Yelenna Skomorovska-Prokvolit, David Midem, Sidney Ogolla, Bjoern B. Burckhardt, Tanja Gangnus, Julio Scharfstein, Celso Caruso-Neves, Owen J.T. McCarty, David Gailani, Michael Bader, Philip J. Rosenthal, Arlene E. Dent, Chris J. Janse, Keith R. McCrae, Ana Acacia de Sa Pinheiro, James W. Kazura, Alvin H. Schmaier
Institutions: Universidade Federal do Rio de Janeiro, Case Western Reserve University, Cleveland Clinic, Kenya Medical Research Institute, University of Münster, Oregon Health & Science University, Vanderbilt University Medical Center, Max Delbrück Center, German Centre for Cardiovascular Research, Charité – Universitätsmedizin Berlin, University of Lübeck, University of California, San Francisco, Leiden University Medical Center
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
OpenAlex ID: W7168269858