title: A role for apical membrane antigen 1 during invasion of hepatocytes by Plasmodium falciparum sporozoites.
abstract: Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and invade hepatocytes as a first and obligatory step of the parasite life cycle in man. Hepatocyte invasion involves proteins secreted from parasite vesicles called micronemes, the most characterized being the thrombospondin-related adhesive protein (TRAP). Here we investigated the expression and function of another microneme protein recently identified in Plasmodium falciparum sporozoites, apical membrane antigen 1 (AMA-1). P. falciparum AMA-1 is expressed in sporozoites and is lost after invasion of hepatocytes, and anti-AMA-1 antibodies inhibit sporozoite invasion, suggesting that the protein is involved during invasion of hepatocytes. As observed with TRAP, AMA-1 is initially mostly sequestered within the sporozoite. Upon microneme exocytosis, AMA-1 and TRAP relocate to the sporozoite surface, where they are proteolytically cleaved, resulting in the shedding of soluble fragments. A subset of serine protease inhibitors blocks the processing and shedding of both AMA-1 and TRAP and inhibits sporozoite infectivity, suggesting that interfering with sporozoite proteolytic processing may constitute a valuable strategy to prevent hepatocyte infection.
authors.affiliation: INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, 75013 Paris, France. silvie@ext.jussieu.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Silvie
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Franetich
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Charrin
authors.forename: Markus S
authors.initials: MS
authors.lastname: Mueller
authors.forename: Anthony
authors.initials: A
authors.lastname: Siau
authors.forename: Myriam
authors.initials: M
authors.lastname: Bodescot
authors.forename: Eric
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Yupin
authors.initials: Y
authors.lastname: Charoenvit
authors.forename: Clemens H
authors.initials: CH
authors.lastname: Kocken
authors.forename: Alan W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Van Gemert
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000378:metabolism*; D034101:Sporozoites / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D000953:Antigens, Protozoan; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; C069428:thrombospondin-related adhesive protein, protozoan