title: Disruption of the Plasmodium falciparum liver-stage antigen-1 locus causes a differentiation defect in late liver-stage parasites.
abstract: The malaria parasite Plasmodium falciparum infects humans and first targets the liver where liver-stage parasites undergo pre-erythrocytic replication. Liver-stage antigen-1 (LSA-1) is currently the only identified P. falciparum protein for which expression is restricted to liver stages. Yet, the importance of LSA-1 for liver-stage parasite development remains unknown. Here we deleted LSA-1 in the NF54 strain of P. falciparum and analysed the lsa-1(-) parasites throughout their life cycle. lsa-1(-) sporozoites had normal gliding motility and invasion into hepatocytes. Six days after infection of a hepatocytic cell line, lsa-1(-) parasites exhibited a moderate phenotype with an ~50% reduction of late liver-stage forms when compared with wild type. Strikingly, lsa-1(-) parasites growing in SCID/Alb-uPA mice with humanized livers showed a severe defect in late liver-stage differentiation and exo-erythrocytic merozoite formation 7 days after infection, a time point when wild-type parasites develop into mature merozoites. The lsa-1(-) parasites also showed aberrant liver-stage expression of key parasite proteins apical membrane antigen-1 and circumsporozoite protein. Our data show that LSA-1 plays a critical role during late liver-stage schizogony and is thus important in the parasite transition from the liver to blood. LSA-1 is the first P. falciparum protein identified to be required for this transitional stage of the parasite life cycle.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.forename: John B
authors.initials: JB
authors.lastname: Sacci
authors.forename: Patricia
authors.initials: P
authors.lastname: De La Vega
authors.forename: Nelly
authors.initials: N
authors.lastname: Camargo
authors.forename: Kelly
authors.initials: K
authors.lastname: VanBuskirk
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D017353:Gene Deletion; D022781:Hepatocytes / Q000469:parasitology; D006801:Humans; D052940:Merozoites / Q000254:growth & development; D051379:Mice; D016513:Mice, SCID; D010963:Plasmodium falciparum / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D034101:Sporozoites / Q000254:growth & development
chemical_list: D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C067302:liver stage-specific antigen, Plasmodium