The P-glycoprotein inhibitor GF120918 modulates Ca2+-dependent processes and lipid metabolism in Toxoplasma gondii.
Up-regulation of the membrane-bound efflux pump P-glycoprotein (P-gp) is associated with the phenomenon of multidrug-resistance in pathogenic organisms, including protozoan parasites. In addition, P-gp plays a role in normal physiological processes, however our understanding of these P-gp functions remains limited. In this study we investigated the effects of the P-gp inhibitor GF120918 in Toxoplasma gondii, a model apicomplexan parasite and an important human pathogen. We found that GF120918 treatment severely inhibited parasite invasion and replication. Further analyses of the molecular mechanisms involved revealed that the P-gp inhibitor modulated parasite motility, microneme secretion and egress from the host cell, all cellular processes known to depend on Ca2+ signaling in the parasite. In support of a potential role of P-gp in Ca2+-mediated processes, immunoelectron and fluorescence microscopy showed that T. gondii P-gp was localized in acidocalcisomes, the major Ca2+ storage in the parasite, at the plasma membrane, and in the intravacuolar tubular network. In addition, metabolic labeling of extracellular parasites revealed that inhibition or down-regulation of T. gondii P-gp resulted in aberrant lipid synthesis. These results suggest a crucial role of T. gondii P-gp in essential processes of the parasite biology and further validate the potential of P-gp activity as a target for drug development.
Bottova
Iveta
I
Institute of Parasitology, University of Zurich, Zurich, Switzerland.
Sauder
Ursula
U
Olivieri
Vesna
V
Hehl
Adrian B
AB
Sonda
Sabrina
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014122:Toxoplasma / Q000378:metabolism* / Q000472:pathogenicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; C083501:Elacridar
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