Plasmodium falciparum-induced severe
malaria remains a continuing problem in areas of endemicity, with elevated morbidity and mortality. Drugs targeting mechanisms involved in severe
malaria pathology, including cytoadhesion of infected red blood cells (RBCs) to host receptors and production of proinflammatory
cytokines, are still necessary. Human C1-inhibitor (C1INH) is a multifunctional
protease inhibitor that regulates coagulation, vascular permeability, and
inflammation, with beneficial effects in inflammatory disease models, including
septic shock. We found that human C1INH, at therapeutically relevant doses, blocks severe
malaria pathogenic processes by 2 distinct mechanisms. First, C1INH bound to
glycan moieties within P. falciparum
glycosylphosphatidylinositol (PfGPI) molecules on the parasite surface, inhibiting parasite RBC invasion and proinflammatory
cytokine production by parasite-stimulated monocytes in vitro and reducing
parasitemia in a rodent model of experimental
cerebral malaria (ECM) in vivo. Second, C1INH bound to host CD36 and
chondroitin sulfate A molecules, interfering with cytoadhesion of infected RBCs by competitive binding to these receptors in vitro and reducing sequestration in specific tissues and protecting against ECM in vivo. This study reveals that C1INH is a potential therapeutic
antimalarial molecule able to interfere with severe-disease etiology at multiple levels through specific interactions with both parasite PfGPIs and host cell receptors.