title: The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels ofvarGenes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1.
abstract: By attaching infected erythrocytes to the vascular lining,Plasmodium falciparumparasites leave blood circulation and avoid splenic clearance. This sequestration is central to pathogenesis. Severe malaria is associated with parasites expressing an antigenically distinctP. falciparumerythrocyte membrane protein 1 (PfEMP1) subset mediating binding to endothelial receptors. Previous studies indicate that PfEMP1 adhesins with so-called CIDRα1 domains capable of binding endothelial protein C receptor (EPCR) constitute the PfEMP1 subset associated with severe pediatric malaria. To analyze the relative importance of different subtypes of CIDRα1 domains, we compared Pfemp1transcript levels in children with severe malaria (including 9 fatal and 114 surviving cases), children hospitalized with uncomplicated malaria (n= 42), children with mild malaria not requiring hospitalization (n= 10), and children with parasitemia and no ongoing fever (n= 12). High levels of transcripts encoding EPCR-binding PfEMP1 were found in patients with symptomatic infections, and the abundance of these transcripts increased with disease severity. The compositions of CIDRα1 subtype transcripts varied markedly between patients, and none of the subtypes were dominant. Transcript-level analyses targeting other domain types indicated that subtypes of DBLβ or DBLζ domains might mediate binding phenomena that, in conjunction with EPCR binding, could contribute to pathogenesis. These observations strengthen the rationale for targeting the PfEMP1-EPCR interaction by vaccines and adjunctive therapies. Interventions should target EPCR binding of all CIDRα1 subtypes.
authors.affiliation: Kilimanjaro Christian Medical University College and Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors.forename: Sixbert I
authors.initials: SI
authors.lastname: Mkumbaye
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.affiliation: National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania.
authors.forename: Eric
authors.initials: E
authors.lastname: Lyimo
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.affiliation: National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania.
authors.forename: Alphaxard
authors.initials: A
authors.lastname: Manjurano
authors.affiliation: National Institute for Medical Research, Mwanza Research Centre, Mwanza, Tanzania.
authors.forename: Jacklin
authors.initials: J
authors.lastname: Mosha
authors.affiliation: Kilimanjaro Christian Medical University College and Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors.forename: Reginald A
authors.initials: RA
authors.lastname: Kavishe
authors.affiliation: Kilimanjaro Christian Medical University College and Kilimanjaro Clinical Research Institute, Moshi, Tanzania.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Mwakalinga
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.
authors.forename: Daniel T R
authors.initials: DTR
authors.lastname: Minja
authors.affiliation: National Institute for Medical Research, Tanga Research Centre, Tanga, Tanzania.
authors.forename: John P
authors.initials: JP
authors.lastname: Lusingu
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology and Microbiology, University of Copenhagen, and 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 International Health, Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark thomasl@sund.ku.dk.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-3044-4249
authors.initials: T
authors.lastname: Lavstsen
mesh_terms: D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000276:immunology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology; D054730:Protein Interaction Domains and Motifs; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D012720:Severity of Illness Index; D013636:Tanzania; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: PfEMP1; Plasmodium falciparum; antigenic variation; gene expression; malaria