Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.
Members of the Plasmodium falciparum var gene family encode clonally variant adhesins, which play an important role in the pathogenicity of tropical malaria. Here we employ a selective panning protocol to generate isogenic P.falciparum populations with defined adhesive phenotypes for CD36, ICAM-1 and CSA, expressing single and distinct var gene variants. This technique has established the framework for examining var gene expression, its regulation and switching. It was found that var gene switching occurs in situ. Ubiquitous transcription of all var gene variants appears to occur in early ring stages. However, var gene expression is tightly regulated in trophozoites and is exerted through a silencing mechanism. Transcriptional control is mutually exclusive in parasites that express defined adhesive phenotypes. In situ var gene switching is apparently mediated at the level of transcriptional initiation, as demonstrated by nuclear run-on analyses. Our results suggest that an epigenetic mechanism(s) is involved in var gene regulation.
Scherf
A
A
Unité de Biologie des Interactions Hôte-Parasite, CNRS URA 1960, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. ascherf@pasteur.fr
Hernandez-Rivas
R
R
Buffet
P
P
Bottius
E
E
Benatar
C
C
Pouvelle
B
B
Gysin
J
J
Lanzer
M
M
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation / Q000235:genetics*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001921:Brain; D016466:CHO Cells; D002448:Cell Adhesion / Q000235:genetics*; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000378:metabolism; D006224:Cricetinae; D004727:Endothelium / Q000166:cytology; D004912:Erythrocytes / Q000469:parasitology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D017125:Genes, Protozoan; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009244:NAD+ Nucleosidase / Q000378:metabolism; D010963:Plasmodium falciparum / Q000166:cytology / Q000235:genetics* / Q000472:pathogenicity; D012333:RNA, Messenger / Q000032:analysis; D016053:RNA, Protozoan / Q000032:analysis; D012453:Saimiri; D014158:Transcription, Genetic / Q000235:genetics*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016053:RNA, Protozoan; D018799:Intercellular Adhesion Molecule-1; D002809:Chondroitin Sulfates; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1