title: Vital and dispensable roles of Plasmodium multidrug resistance transporters during blood- and mosquito-stage development.
abstract: Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of malaria parasites. Four P. berghei genes (encoding MDR1, 4, 6 and 7) were refractory to deletion, indicating a vital role during blood stage multiplication and validating them as potential targets for antimalarial drugs. Mutants lacking expression of MDR2, MDR3 and MDR5 were generated in both P. berghei and P. falciparum, indicating a dispensable role for blood stage development. Whereas P. berghei mutants lacking MDR3 and MDR5 had a reduced blood stage multiplication in vivo, blood stage growth of P. falciparum mutants in vitro was not significantly different. Oocyst maturation and sporozoite formation in Plasmodium mutants lacking MDR2 or MDR5 was reduced. Sporozoites of these P. berghei mutants were capable of infecting mice and life cycle completion, indicating the absence of vital roles during liver stage development. Our results demonstrate vital and dispensable roles of MDR proteins during blood stages and an important function in sporogony for MDR2 and MDR5 in both Plasmodium species.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Sanna R
authors.initials: SR
authors.lastname: Rijpma
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van der Velden
authors.affiliation: Department of Tropical Medicine, The Jikei University School of Medicine, Post code 105-8461 Nishi-shinbashi 3-25-8, Minato-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Annoura
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Matz
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Sanketha
authors.initials: S
authors.lastname: Kenthirapalan
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.|Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Taco W A
authors.identifier: 0000-0002-8547-7523
authors.initials: TW
authors.lastname: Kooij
authors.affiliation: Parasitology Unit, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.|Institute of Biology, Humboldt University, 10117, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: van de Vegte-Bolmer
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: Siebelink-Stoter
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Graumans
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Ramesar
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: Onny
authors.initials: O
authors.lastname: Klop
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.affiliation: Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
authors.forename: Blandine M
authors.initials: BM
authors.lastname: Franke-Fayard
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Geert-Grooteplein 28, 6525, GA, Nijmegen, The Netherlands.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D009033:Culicidae / Q000469:parasitology*; D018432:Drug Resistance, Multiple; D005260:Female; D008018:Life Cycle Stages; D008288:Malaria / Q000469:parasitology; D016778:Malaria, Falciparum / Q000469:parasitology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D034101:Sporozoites / Q000378:metabolism
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum