title: Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites.
abstract: Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed.
authors.affiliation: Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Ashworth Laboratory, Kings Buildings, Edinburgh EH9 3JT, UK. Paul.Hunt@ed.ac.uk
authors.forename: Paul
authors.initials: P
authors.lastname: Hunt
authors.forename: Ana
authors.initials: A
authors.lastname: Afonso
authors.forename: Alison
authors.initials: A
authors.lastname: Creasey
authors.forename: Richard
authors.initials: R
authors.lastname: Culleton
authors.forename: Amar Bir Singh
authors.initials: AB
authors.lastname: Sidhu
authors.forename: John
authors.initials: J
authors.lastname: Logan
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Valderramos
authors.forename: Iain
authors.initials: I
authors.lastname: McNae
authors.forename: Sandra
authors.initials: S
authors.lastname: Cheesman
authors.forename: Virgilio
authors.initials: V
authors.lastname: do Rosario
authors.forename: Richard
authors.initials: R
authors.lastname: Carter
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Pedro
authors.initials: P
authors.lastname: Cravo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D017125:Genes, Protozoan; D006801:Humans; D051379:Mice; D008808:Mice, Inbred CBA; D008958:Models, Molecular; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D025801:Ubiquitin; D000077332:Artesunate; D002738:Chloroquine; C031327:artemisinin