Multidrug ATP-binding cassette transporters are essential for hepatic development of Plasmodium sporozoites.
Multidrug resistance-associated proteins (MRPs) belong to the C-family of ATP-binding cassette (ABC) transport proteins and are known to transport a variety of physiologically important compounds and to be involved in the extrusion of pharmaceuticals. Rodent malaria parasites encode a single ABC transporter subfamily C protein, whereas human parasites encode two: MRP1 and MRP2. Although associated with drug resistance, their biological function and substrates remain unknown. To elucidate the role of MRP throughout the parasite life cycle, Plasmodium berghei and Plasmodium falciparum mutants lacking MRP expression were generated. P. berghei mutants lacking expression of the single MRP as well as P. falciparum mutants lacking MRP1, MRP2 or both proteins have similar blood stage growth kinetics and drug-sensitivity profiles as wild type parasites. We show that MRP1-deficient parasites readily invade primary human hepatocytes and develop into mature liver stages. In contrast, both P. falciparum MRP2-deficient parasites and P. berghei mutants lacking MRP protein expression abort in mid to late liver stage development, failing to produce mature liver stages. The combined P. berghei and P. falciparum data are the first demonstration of a critical role of an ABC transporter during Plasmodium liver stage development.
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Sanna R
SR
Rijpma
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Maarten
M
van der Velden
Department of Microbiology and Medical Zoology, University of Puerto Rico, School of Medicine, PR 00936-5067, San Juan, Puerto Rico, USA.
Maria
M
González-Pons
Department of Tropical Medicine, The Jikei University School of Medicine, Post code 105-8461, Nishi-shinbashi 3-25-8, Minato-ku, Tokyo, Japan.
Takeshi
T
Annoura
Department of Medical Microbiology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Ben C L
BC
van Schaijk
Department of Medical Microbiology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Geert-Jan
GJ
van Gemert
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Jeroen J M W
JJ
van den Heuvel
Department of Parasitology, Center of Infectious Diseases, Leiden Malaria Research Group, Leiden, The Netherlands.
Jai
J
Ramesar
Department of Parasitology, Center of Infectious Diseases, Leiden Malaria Research Group, Leiden, The Netherlands.
Severine
S
Chevalley-Maurel
Department of Medical Microbiology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Ivo H
IH
Ploemen
Department of Tropical Medicine, The Jikei University School of Medicine, Post code 105-8461, Nishi-shinbashi 3-25-8, Minato-ku, Tokyo, Japan.
Shahid M
SM
Khan
AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service Parasitologie-Mycologie, 47-83 Boulevard de l'Hôpital, 75651, Paris, France.
Jean-Francois
JF
Franetich
AP-HP, Groupe hospitalier Pitié-Salpêtrière, Service Parasitologie-Mycologie, 47-83 Boulevard de l'Hôpital, 75651, Paris, France.|CIMI-Paris (UPMC UMRS CR7 - Inserm U1135 - CNRS ERL 8255), Paris, France.
Dominique
D
Mazier
Department of Surgery, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
Johannes H W
JH
de Wilt
Department of Microbiology and Medical Zoology, University of Puerto Rico, School of Medicine, PR 00936-5067, San Juan, Puerto Rico, USA.
Adelfa E
AE
Serrano
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Frans G M
FG
Russel
Department of Parasitology, Center of Infectious Diseases, Leiden Malaria Research Group, Leiden, The Netherlands.
Chris J
CJ
Janse
Department of Medical Microbiology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Robert W
RW
Sauerwein
Department of Pharmacology and Toxicology, Radboud University Medical Centre, Geert-Grooteplein 28, 6525 GA, Nijmegen, The Netherlands.
Jan B
JB
Koenderink
Department of Parasitology, Center of Infectious Diseases, Leiden Malaria Research Group, Leiden, The Netherlands.
Blandine M
BM
Franke-Fayard
D000818:Animals; D030801:Animals, Genetically Modified; D000962:Antimalarials / Q000494:pharmacology; D001769:Blood / Q000469:parasitology; D005260:Female; D022781:Hepatocytes / Q000469:parasitology; D006790:Host-Parasite Interactions; D006801:Humans; D008099:Liver / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010962:Plasmodium berghei / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D034101:Sporozoites / Q000378:metabolism / Q000502:physiology*
D000962:Antimalarials; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins