Human C1-Inhibitor Suppresses Malaria Parasite Invasion and Cytoadhesion via Binding to Parasite Glycosylphosphatidylinositol and Host Cell Receptors

The Journal of Infectious Diseases
Pedro MejiaJames R Mitchell

Abstract

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 ...Continue Reading

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Citations

May 10, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alexander T KennedyWai-Hong Tham
Dec 17, 2019·Immunological Reviews·Katherine R DobbsArlene E Dent
Mar 18, 2020·FEBS Letters·Patience Kerubo KiyukaAyman Khattab
Jul 3, 2020·Malaria Journal·Isaclaudia G de Azevedo-QuintanilhaHugo C Castro-Faria-Neto
Aug 1, 2020·Frontiers in Immunology·Jack MellorsMiles Carroll
Apr 6, 2019·Frontiers in Microbiology·Shuai ShaoXinping Zhu
May 27, 2021·The Journal of Venomous Animals and Toxins Including Tropical Diseases·Claudia Demarta-Gatsi, Salah Mécheri

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