title: Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass.
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.
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109;
authors.forename: Maria
authors.initials: M
authors.lastname: Bernabeu
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109;
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Danziger
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109;
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.affiliation: Department of Medicine, Goa Medical College & Hospital, Bambolim, Goa 403202, India;
authors.forename: Marina
authors.initials: M
authors.lastname: Vaz
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Prasad H
authors.initials: PH
authors.lastname: Babar
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brazier
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Thurston
authors.initials: T
authors.lastname: Herricks
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Maki
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Ligia
authors.initials: L
authors.lastname: Pereira
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mascarenhas
authors.affiliation: Department of Medicine, Goa Medical College & Hospital, Bambolim, Goa 403202, India;
authors.forename: Edwin
authors.initials: E
authors.lastname: Gomes
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Laura
authors.initials: L
authors.lastname: Chery
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109;
authors.forename: John D
authors.initials: JD
authors.lastname: Aitchison
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195; Department of Global Health, University of Washington, Seattle, WA 98195.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109; joe.smith@cidresearch.org.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018533:Biomass; D000074283:Endothelial Protein C Receptor; D005260:Female; D006801:Humans; D000069550:Machine Learning; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000235:genetics* / Q000472:pathogenicity*; D011486:Protein C / Q000378:metabolism; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014774:Virulence; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: EPCR; PfEMP1; Plasmodium falciparum; malaria; var