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

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 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.
AuthorsPedro Mejia, Monica Diez-Silva, Faustin Kamena, Fengxin Lu, Stacey M Fernandes, Peter H Seeberger, Alvin E Davis 3rd, James R Mitchell
JournalThe Journal of infectious diseases (J Infect Dis) Vol. 213 Issue 1 Pg. 80-9 (Jan 01 2016) ISSN: 1537-6613 [Electronic] United States
PMID26347576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected].
Chemical References
  • Complement C1 Inactivator Proteins
  • Complement C1 Inhibitor Protein
  • Glycosylphosphatidylinositols
  • Protozoan Proteins
  • Recombinant Proteins
  • SERPING1 protein, human
Topics
  • Animals
  • Cell Adhesion (drug effects)
  • Cell Line, Tumor
  • Complement C1 Inactivator Proteins (metabolism, pharmacology)
  • Complement C1 Inhibitor Protein
  • Disease Models, Animal
  • Erythrocytes (parasitology)
  • Female
  • Glycosylphosphatidylinositols (metabolism)
  • Host-Parasite Interactions (drug effects)
  • Humans
  • Malaria, Cerebral (blood, metabolism, parasitology)
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium berghei (metabolism, pathogenicity)
  • Protozoan Proteins (metabolism)
  • Recombinant Proteins (metabolism, pharmacology)

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