Dataset Information

Genetics of mefloquine resistance in the rodent malaria parasite Plasmodium chabaudi.

ABSTRACT: The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene pfmdr1 in Plasmodium falciparum may be involved. Using the rodent malaria model Plasmodium chabaudi, we investigated the role of the orthologue of this gene, pcmdr1, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone. pcmdr1 exists as a single copy gene on chromosome 12 of the sensitive clone. In AS(15MF/3), the gene was found to have undergone duplication, with one copy translocating to chromosome 4. mRNA levels of pcmdr1 were higher in the mutant than in the parent sensitive clone. A partial genetic map of the translocation showed that other genes in addition to pcmdr1 had been cotranslocated. The sequences of both copies of pcmdr1 of AS(15MF/3) were identical to that of the parent sensitive clone. A cross was made between AS(15MF/3) and an unrelated mefloquine-sensitive clone, AJ. Phenotypic and molecular analysis of progeny clones showed that duplication and overexpression of the pcmdr1 gene was an important determinant of resistance. However, not all mefloquine-resistant progeny contained the duplicated gene, showing that at least one other gene was involved in resistance.

SUBMITTER: Cravo PV

PROVIDER: S-EPMC151772 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Genetics of mefloquine resistance in the rodent malaria parasite Plasmodium chabaudi.

Cravo Pedro V L PV Carlton Jane M-R JM Hunt Paul P Bisoni Laura L Padua Rose Ann RA Walliker David D

Antimicrobial agents and chemotherapy 20030201 2

The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene pfmdr1 in Plasmodium falciparum may be involved. Using the rodent malaria model Plasmodium chabaudi, we investigated the role of the orthologue of this gene, pcmdr1, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone. pcmdr1 exists as a single copy gene on chromosome 12 of the sensi ...[more]

PMID: 12543682

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Project description:BackgroundThe ability of malaria (Plasmodium) parasites to adjust investment into sexual transmission stages versus asexually replicating stages is well known, but plasticity in other traits underpinning the replication rate of asexual stages in the blood has received less attention. Such traits include burst size (the number of merozoites produced per schizont), the duration of the asexual cycle, and invasion preference for different ages of red blood cell (RBC).MethodsHere, plasticity [environment (E) effects] and genetic variation [genotype (G) effects] in traits relating to asexual replication rate are examined for 4 genotypes of the rodent malaria parasite Plasmodium chabaudi. An experiment tested whether asexual dynamics differ between parasites infecting control versus anaemic hosts, and whether variation in replication rate can be explained by differences in burst size, asexual cycle, and invasion rates.ResultsThe within-host environment affected each trait to different extents but generally had similar impacts across genotypes. The dynamics of asexual densities exhibited a genotype by environment effect (G×E), in which one of the genotypes increased replication rate more than the others in anaemic hosts. Burst size and cycle duration varied between the genotypes (G), while burst size increased and cycle duration became longer in anaemic hosts (E). Variation in invasion rates of differently aged RBCs was not explained by environmental or genetic effects. Plasticity in burst size and genotype are the only traits making significant contributions to the increase in asexual densities observed in anaemic hosts, together explaining 46.4% of the variation in replication rate.ConclusionsThat host anaemia induces several species of malaria parasites to alter conversion rate is well documented. Here, previously unknown plasticity in other traits underpinning asexual replication is revealed. These findings contribute to mounting evidence that malaria parasites deploy a suite of sophisticated strategies to maximize fitness by coping with, or exploiting the opportunities provided by, the variable within-host conditions experienced during infections. That genetic variation and genotype by environment interactions also shape these traits highlights their evolutionary potential. Asexual replication rate is a major determinant of virulence and so, understanding the evolution of virulence requires knowledge of the ecological (within-host environment) and genetic drivers of variation among parasites.

Project description:BackgroundPlasmodium falciparum, has developed resistance to many of the drugs in use. The recommended treatment policy is now to use drug combinations. The atovaquone-proguanil (AP) drug combination, is one of the treatment and prophylaxis options. Atovaquone (ATQ) exerts its action by inhibiting plasmodial mitochondria electron transport at the level of the cytochrome bc1 complex. Plasmodium falciparum in vitro resistance to ATQ has been associated with specific point mutations in the region spanning codons 271-284 of the cytochrome b gene. ATQ -resistant Plasmodium yoelii and Plasmodium berghei lines have been obtained and resistant lines have amino acid mutations in their CYT b protein sequences. Plasmodium chabaudi model for studying drug-responses and drug-resistance selection is a very useful rodent malaria model but no ATQ resistant parasites have been reported so far. The aim of this study was to determine the ATQ sensitivity of the P. chabaudi clones, to select a resistant parasite line and to perform genotypic characterization of the cytb gene of these clones.MethodsTo select for ATQ resistance, Plasmodium. chabaudi chabaudi clones were exposed to gradually increasing concentrations of ATQ during several consecutive passages in mice. Plasmodium chabaudi cytb gene was amplified and sequenced.ResultsATQ resistance was selected from the clone AS-3CQ. In order to confirm whether an heritable genetic mutation underlies the response of AS-ATQ to ATQ, the stability of the drug resistance phenotype in this clone was evaluated by measuring drug responses after (i) multiple blood passages in the absence of the drug, (ii) freeze/thawing of parasites in liquid nitrogen and (iii) transmission through a mosquito host, Anopheles stephensi. ATQ resistance phenotype of the drug-selected parasite clone kept unaltered. Therefore, ATQ resistance in clone AS-ATQ is genetically encoded. The Minimum Curative Dose of AS-ATQ showed a six-fold increase in MCD to ATQ relative to AS-3CQ.ConclusionsA mutation was found on the P. chabaudi cytb gene from the AS-ATQ sample a substitution at the residue Tyr268 for an Asn, this mutation is homologous to the one found in P. falciparum isolates resistant to ATQ.

Dataset Information

Genetics of mefloquine resistance in the rodent malaria parasite Plasmodium chabaudi.

Publications

Genetics of mefloquine resistance in the rodent malaria parasite Plasmodium chabaudi.

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