title: Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children.
abstract: The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, Faculty of Health Sciences, University of Copenhagen, Rigshospitalet, 1014 Copenhagen K, Denmark. thomasl@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Fredy
authors.initials: F
authors.lastname: Saguti
authors.forename: Pamela
authors.initials: P
authors.lastname: Magistrado
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rask
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.forename: Sanne S
authors.initials: SS
authors.lastname: Berger
authors.forename: Vito
authors.initials: V
authors.lastname: Baraka
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Marquard
authors.forename: Andaine
authors.initials: A
authors.lastname: Seguin-Orlando
authors.forename: Eske
authors.initials: E
authors.lastname: Willerslev
authors.forename: M Thomas P
authors.initials: MT
authors.lastname: Gilbert
authors.forename: John
authors.initials: J
authors.lastname: Lusingu
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
mesh_terms: D000818:Animals; D002648:Child; D017125:Genes, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum