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      Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass.

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          Abstract

          The interplay between cellular and molecular determinants that lead to severe malaria in adults is unexplored. Here, we analyzed parasite virulence factors in an infected adult population in India and investigated whether severe malaria isolates impair endothelial protein C receptor (EPCR), a protein involved in coagulation and endothelial barrier permeability. Severe malaria isolates overexpressed specific members of the Plasmodium falciparum var gene/PfEMP1 (P. falciparum erythrocyte membrane protein 1) family that bind EPCR, including DC8 var genes that have previously been linked to severe pediatric malaria. Machine learning analysis revealed that DC6- and DC8-encoding var transcripts in combination with high parasite biomass were the strongest indicators of patient hospitalization and disease severity. We found that DC8 CIDRα1 domains from severe malaria isolates had substantial differences in EPCR binding affinity and blockade activity for its ligand activated protein C. Additionally, even a low level of inhibition exhibited by domains from two cerebral malaria isolates was sufficient to interfere with activated protein C-barrier protective activities in human brain endothelial cells. Our findings demonstrate an interplay between parasite biomass and specific PfEMP1 adhesion types in the development of adult severe malaria, and indicate that low impairment of EPCR function may contribute to parasite virulence.

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          Author and article information

          Journal
          Proc. Natl. Acad. Sci. U.S.A.
          Proceedings of the National Academy of Sciences of the United States of America
          1091-6490
          0027-8424
          Jun 7 2016
          : 113
          : 23
          Affiliations
          [1 ] Center for Infectious Disease Research, Seattle, WA 98109;
          [2 ] Department of Medicine, Goa Medical College & Hospital, Bambolim, Goa 403202, India;
          [3 ] Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
          [4 ] Center for Infectious Disease Research, Seattle, WA 98109; joe.smith@cidresearch.org.
          Article
          1524294113
          10.1073/pnas.1524294113
          27185931
          73aa9c59-299b-433a-80b6-567b05959a27
          History

          EPCR,PfEMP1,Plasmodium falciparum,malaria,var
          EPCR, PfEMP1, Plasmodium falciparum, malaria, var

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