A Role for Apical Membrane Antigen 1 during Invasion of Hepatocytes by Plasmodium falciparum Sporozoites

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 thrombospo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-03, Vol.279 (10), p.9490-9496
Main Authors: Silvie, Olivier, Franetich, Jean-François, Charrin, Stéphanie, Mueller, Markus S., Siau, Anthony, Bodescot, Myriam, Rubinstein, Eric, Hannoun, Laurent, Charoenvit, Yupin, Kocken, Clemens H., Thomas, Alan W., van Gemert, Geert-Jan, Sauerwein, Robert W., Blackman, Michael J., Anders, Robin F., Pluschke, Gerd, Mazier, Dominique
Format: Article
Language:English
Subjects:
Animals
Antigens, Protozoan - metabolism
apical membrane antigen 1
Cells, Cultured
Culicidae
Hepatocytes - metabolism
Hepatocytes - parasitology
Humans
Membrane Proteins - metabolism
micronemes
Plasmodium falciparum
Plasmodium falciparum - metabolism
Plasmodium falciparum - pathogenicity
Protozoan Proteins - metabolism
Sporozoites - metabolism
Sporozoites - pathogenicity
thrombospondin-related adhesive protein
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M311331200