title: Evidence that mutant PfCRT facilitates the transmission to mosquitoes of chloroquine-treated Plasmodium gametocytes.
abstract: Resistance of the human malarial parasite Plasmodium falciparum to the antimalarial drug chloroquine has rapidly spread from several independent origins and is now widely prevalent throughout the majority of malaria-endemic areas. Field studies have suggested that chloroquine-resistant strains might be more infective to mosquito vectors. To test the hypothesis that the primary chloroquine resistance determinant, mutations in PfCRT, facilitates parasite transmission under drug pressure, we have introduced a mutant or wild-type pfcrt allele into the rodent model malarial parasite Plasmodium berghei. Our results show that mutant PfCRT from the chloroquine-resistant 7G8 strain has no effect on asexual blood stage chloroquine susceptibility in vivo or ex vivo but confers a significant selective advantage in competitive mosquito infections in the presence of this drug, by protecting immature gametocytes from its lethal action. Enhanced infectivity to mosquitoes may have been a key factor driving the worldwide spread of mutant pfcrt.
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ecker
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Lakshmanan
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology*; D009033:Culicidae / Q000469:parasitology*; D004195:Disease Models, Animal; D004351:Drug Resistance; D005260:Female; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects / Q000302:isolation & purification* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000235:genetics*; D014774:Virulence
chemical_list: D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine