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.
Highlights
Malaria is estimated to cause the death of over one million people annually, mainly children in Africa
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
Summary
Malaria is estimated to cause the death of over one million people annually, mainly children in Africa. One major factor has been the emergence and spread of malaria parasites which are resistant to antimalarial drugs such as chloroquine or pyrimethamine/sulphadoxine. Many countries have introduced artemisinin (ART) derivatives as their first-line therapy, in combination with other drugs (such as mefloquine, amodiaquine, piperaquine, pyrimethamine/sulphadoxine or lumefantrine) (World Health Organization, 2006). These artemisinin combination therapies (ACTs) present favourable pharmacokinetics and are thought to reduce the probability of mutations that underlie resistance and treatment failure emerging in parasite populations (White, 1999). The activation of the endoperoxide group might produce a AS
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