title: Plasmodium falciparum antigenic variation: relationships between widespread endothelial activation, parasite PfEMP1 expression and severe malaria.
abstract: BACKGROUND
  Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) is a family of variant surface antigens (VSA) that mediate the adhesion of parasite infected erythrocytes to capillary endothelial cells within host tissues. Opinion is divided over the role of PfEMP1 in the widespread endothelial activation associated with severe malaria. In a previous study we found evidence for differential associations between defined VSA subsets and specific syndromes of severe malaria: group A-like PfEMP1 expression and the "rosetting" phenotype were associated with impaired consciousness and respiratory distress, respectively. This study explores the involvement of widespread endothelial activation in these associations.
  
  
  METHODS
  We used plasma angiopoietin-2 as a marker of widespread endothelial activation. Using logistic regression analysis, we explored the relationships between plasma angiopoietin-2 levels, parasite VSA expression and the two syndromes of severe malaria, impaired consciousness and respiratory distress.
  
  
  RESULTS
  Plasma angiopoietin-2 was associated with both syndromes. The rosetting phenotype did not show an independent association with respiratory distress when adjusted for angiopoietin-2, consistent with a single pathogenic mechanism involving widespread endothelial activation. In contrast, group A-like PfEMP1 expression and angiopoietin-2 maintained independent associations with impaired consciousness when adjusted for each other.
  
  
  CONCLUSIONS
  The results are consistent with multiple pathogenic mechanisms leading to severe malaria and heterogeneity in the pathophysiology of impaired consciousness. The observed association between group A-like PfEMP1 and impaired consciousness does not appear to involve widespread endothelial activation.
authors.affiliation: KEMRI-Wellcome Trust Research Programme, P,O, Box 230-80108, Kilifi, Kenya. aabdi@kemri-wellcome.org.
authors.forename: Abdirahman I
authors.initials: AI
authors.lastname: Abdi
authors.forename: Gregory
authors.initials: G
authors.lastname: Fegan
authors.forename: Michelle
authors.initials: M
authors.lastname: Muthui
authors.forename: Esther
authors.initials: E
authors.lastname: Kiragu
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Musyoki
authors.forename: Michael
authors.initials: M
authors.lastname: Opiyo
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: George M
authors.initials: GM
authors.lastname: Warimwe
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bull
mesh_terms: D042702:Angiopoietin-2 / Q000097:blood; D000940:Antigenic Variation; D002648:Child; D004727:Endothelium / Q000276:immunology; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology / Q000469:parasitology*; D018512:Parasitemia / Q000097:blood / Q000276:immunology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000276:immunology / Q000469:parasitology; D012397:Rosette Formation
chemical_list: D042702:Angiopoietin-2; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum