title: Dissection of the role of PfEMP1 and ICAM-1 in the sensing of Plasmodium-falciparum-infected erythrocytes by natural killer cells.
abstract: BACKGROUND
  Host innate immunity contributes to malaria clinical outcome by providing protective inflammatory cytokines such as interferon-gamma, and by shaping the adaptive immune response. Plasmodium falciparum (Pf) is the etiologic agent of the most severe forms of human malaria. Natural Killer (NK) cells are lymphocytes of the innate immune system that are the first effectors to produce interferon-gamma in response to Pf. However, the molecular bases of Pf-NK cell recognition events are unknown. Our study focuses on the role of Pf erythrocyte membrane protein 1 (PfEMP1), a major Pf virulence factor. PfEMP1 is expressed on parasitized-erythrocytes and participates to vascular obstruction through the binding to several host receptors. PfEMP1 is also a pivotal target for host antibody response to Pf infection.
  
  
  RESULTS
  Using genetically-engineered parasite mutant strains, a human genetic deficiency, and blocking antibodies, we identified two receptor-ligand pairs involved in two uncoupled events occurring during the sensing of Pf infection by NK cells. First, PfEMP1 interaction with one of its host receptor, chondroitin sulfate A, mediates the cytoadhesion of Pf-infected erythrocytes to human NK cell lines, but is not required for primary NK cell activation. Second, intercellular adhesion molecule-1 (ICAM-1), another host receptor for PfEMP1, is mandatory for NK cell interferon-gamma response. In this case, ICAM-1 acts via its engagement with its host ligand, LFA-1, and not with PfEMP1, consistent with the obligatory cross-talk of NK cells with macrophages for their production of interferon-gamma.
  
  
  CONCLUSIONS
  PfEMP1-independent but ICAM-1/LFA-1-dependent events occurring during NK cell activation by Pf highlight the fundamental role of cellular cooperation during innate immune response to malaria.
authors.affiliation: Aix-Marseille Université, Faculté des Sciences de Luminy, Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baratin
authors.forename: Sophie
authors.initials: S
authors.lastname: Roetynck
authors.forename: Bruno
authors.initials: B
authors.lastname: Pouvelle
authors.forename: Céline
authors.initials: C
authors.lastname: Lemmers
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Viebig
authors.forename: Sofia
authors.initials: S
authors.lastname: Johansson
authors.forename: Philippe
authors.initials: P
authors.lastname: Bierling
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.forename: Jürg
authors.initials: J
authors.lastname: Gysin
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Sophie
authors.initials: S
authors.lastname: Ugolini
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D007113:Immunity, Innate; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D016778:Malaria, Falciparum / Q000097:blood / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015800:Protozoan Proteins / Q000502:physiology*; D014774:Virulence / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D002809:Chondroitin Sulfates