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Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring.

Pollitt LC, Sim D, Salathé R, Read AF - Evol Appl (2014)

Bottom Line: Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment.Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system.This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University University Park, PA, USA ; Centre for Immunity, Infection and Evolution, University of Edinburgh Edinburgh, UK.

ABSTRACT
Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing 'resistant' parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

No MeSH data available.


Related in: MedlinePlus

Infection dynamics in treated and untreated infections. Lines show the mean from four or five independent infections of each of five parasite clones (denoted AJ, AQ, AS (pry R), AS (wt) and ER). Error bars show the standard error of the mean. In drug-treated infections, mice received 8 mg/kg artesunate twice a day on days 6–10 PI. Area of grey shading indicates the period of drug treatment.
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fig01: Infection dynamics in treated and untreated infections. Lines show the mean from four or five independent infections of each of five parasite clones (denoted AJ, AQ, AS (pry R), AS (wt) and ER). Error bars show the standard error of the mean. In drug-treated infections, mice received 8 mg/kg artesunate twice a day on days 6–10 PI. Area of grey shading indicates the period of drug treatment.

Mentions: Over the entire period of monitoring, infection dynamics depended on both the parasite genotype and the interaction between genotype and treatment (parasite ID × drug × day: = 744.2, P < 0.001; Fig.1; Table S1.1). Therefore, we split our data to examine, for treated infections, (i) parasite clearance during treatment, and (ii) parasite recrudescence post-treatment.


Understanding genetic variation in in vivo tolerance to artesunate: implications for treatment efficacy and resistance monitoring.

Pollitt LC, Sim D, Salathé R, Read AF - Evol Appl (2014)

Infection dynamics in treated and untreated infections. Lines show the mean from four or five independent infections of each of five parasite clones (denoted AJ, AQ, AS (pry R), AS (wt) and ER). Error bars show the standard error of the mean. In drug-treated infections, mice received 8 mg/kg artesunate twice a day on days 6–10 PI. Area of grey shading indicates the period of drug treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380923&req=5

fig01: Infection dynamics in treated and untreated infections. Lines show the mean from four or five independent infections of each of five parasite clones (denoted AJ, AQ, AS (pry R), AS (wt) and ER). Error bars show the standard error of the mean. In drug-treated infections, mice received 8 mg/kg artesunate twice a day on days 6–10 PI. Area of grey shading indicates the period of drug treatment.
Mentions: Over the entire period of monitoring, infection dynamics depended on both the parasite genotype and the interaction between genotype and treatment (parasite ID × drug × day: = 744.2, P < 0.001; Fig.1; Table S1.1). Therefore, we split our data to examine, for treated infections, (i) parasite clearance during treatment, and (ii) parasite recrudescence post-treatment.

Bottom Line: Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment.Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system.This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University University Park, PA, USA ; Centre for Immunity, Infection and Evolution, University of Edinburgh Edinburgh, UK.

ABSTRACT
Artemisinin-based drugs are the front-line weapon in the treatment of human malaria cases, but there is concern that recent reports of slow clearing infections may signal developing resistance to treatment. In the absence of molecular markers for resistance, current efforts to monitor drug efficacy are based on the rate at which parasites are cleared from infections. However, some knowledge of the standing variation in parasite susceptibility is needed to identify a meaningful increase in infection half-life. Here, we show that five previously unexposed genotypes of the rodent malaria parasite Plasmodium chabaudi differ substantially in their in vivo response to treatment. Slower clearance rates were not linked to parasite virulence or growth rate, going against the suggestion that drug treatment will drive the evolution of virulence in this system. The level of variation observed here in a relatively small number of genotypes suggests existing 'resistant' parasites could be present in the population and therefore, increased parasite clearance rates could represent selection on pre-existing variation rather than de novo resistance events. This has implications for resistance monitoring as susceptibility may depend on evolved traits unrelated to drug exposure.

No MeSH data available.


Related in: MedlinePlus