title: Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains.
abstract: Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR-binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full-length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1-EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction.
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jakob S
authors.identifier: 0000-0002-4930-5900
authors.initials: JS
authors.lastname: Jespersen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Kilimanjaro Christian Medical University College, Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors.forename: Sixbert I
authors.initials: SI
authors.lastname: Mkumbaye
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.
authors.forename: Daniel Tr
authors.initials: DT
authors.lastname: Minja
authors.affiliation: Centre for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jens Ev
authors.initials: JE
authors.lastname: Petersen
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.
authors.forename: John Pa
authors.initials: JP
authors.lastname: Lusingu
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Centre for Medical Parasitology, Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark thomasl@sund.ku.dk.
authors.forename: Thomas
authors.identifier: 0000-0002-3044-4249
authors.initials: T
authors.lastname: Lavstsen
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D002675:Child, Preschool; D000074283:Endothelial Protein C Receptor; D005260:Female; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000473:pathology*; D008297:Male; D010963:Plasmodium falciparum / Q000235:genetics* / Q000472:pathogenicity*; D011485:Protein Binding; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: CIDR; EPCR; PfEMP1; severe childhood malaria; var