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Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

Bell AS, Huijben S, Paaijmans KP, Sim DG, Chan BH, Nelson WA, Read AF - PLoS ONE (2012)

Bottom Line: Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it.We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes.Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

ABSTRACT
The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

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Transmission parameters.A. Frequency of gametocytes of the resistant clone present in the blood of sham-treated (diamonds) and drug-treated (squares) mice used for mosquito blood feeds. Shaded area indicates timing of treatment. Each data point represents the mean (±1 S.E.M) from six mice. B. Percentage of clone R gametocytes in mouse blood at time of mosquito blood feeds (dark bars) and in mosquito blood-meals fed on those mice (gray bars), for non-drug-treated and drug-treated mice. There were no gametocytes from the resistant clone in untreated mice. C. Prevalence of infection with each clone in mosquitoes fed on each of the six treated and six sham-treated mice. Plotted points are the mean (± SEM) for each mouse across all four feed days, with c.30 mosquitoes per feed. Diamonds, S alleles; squares, R alleles. (2 of 83 infections corresponding to either S or S+R alleles are not included).
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pone-0037172-g003: Transmission parameters.A. Frequency of gametocytes of the resistant clone present in the blood of sham-treated (diamonds) and drug-treated (squares) mice used for mosquito blood feeds. Shaded area indicates timing of treatment. Each data point represents the mean (±1 S.E.M) from six mice. B. Percentage of clone R gametocytes in mouse blood at time of mosquito blood feeds (dark bars) and in mosquito blood-meals fed on those mice (gray bars), for non-drug-treated and drug-treated mice. There were no gametocytes from the resistant clone in untreated mice. C. Prevalence of infection with each clone in mosquitoes fed on each of the six treated and six sham-treated mice. Plotted points are the mean (± SEM) for each mouse across all four feed days, with c.30 mosquitoes per feed. Diamonds, S alleles; squares, R alleles. (2 of 83 infections corresponding to either S or S+R alleles are not included).

Mentions: At the start of drug treatment, resistant parasites constituted less than 0.05% of the parasite and gametocyte populations. After treatment, the population of resistant parasites rapidly expanded (Figure 1– bottom panel, Figure 2– panels G–L), so that the resistant clone became the numerically dominant two days after the cessation of drug treatment (day 11 PI). A day later, the resistant clone made up more than 95% of the parasite population (Figure 3). Drug treatment completely cleared susceptible parasites in only two of the six mice used for mosquito blood feeds (Figure 2– panels I & L). In the other four mice, susceptible parasites were undetectable for 2 to 8 days before they recrudesced to varying degrees (Figure 2– panels G, H, J & K).


Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

Bell AS, Huijben S, Paaijmans KP, Sim DG, Chan BH, Nelson WA, Read AF - PLoS ONE (2012)

Transmission parameters.A. Frequency of gametocytes of the resistant clone present in the blood of sham-treated (diamonds) and drug-treated (squares) mice used for mosquito blood feeds. Shaded area indicates timing of treatment. Each data point represents the mean (±1 S.E.M) from six mice. B. Percentage of clone R gametocytes in mouse blood at time of mosquito blood feeds (dark bars) and in mosquito blood-meals fed on those mice (gray bars), for non-drug-treated and drug-treated mice. There were no gametocytes from the resistant clone in untreated mice. C. Prevalence of infection with each clone in mosquitoes fed on each of the six treated and six sham-treated mice. Plotted points are the mean (± SEM) for each mouse across all four feed days, with c.30 mosquitoes per feed. Diamonds, S alleles; squares, R alleles. (2 of 83 infections corresponding to either S or S+R alleles are not included).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368907&req=5

pone-0037172-g003: Transmission parameters.A. Frequency of gametocytes of the resistant clone present in the blood of sham-treated (diamonds) and drug-treated (squares) mice used for mosquito blood feeds. Shaded area indicates timing of treatment. Each data point represents the mean (±1 S.E.M) from six mice. B. Percentage of clone R gametocytes in mouse blood at time of mosquito blood feeds (dark bars) and in mosquito blood-meals fed on those mice (gray bars), for non-drug-treated and drug-treated mice. There were no gametocytes from the resistant clone in untreated mice. C. Prevalence of infection with each clone in mosquitoes fed on each of the six treated and six sham-treated mice. Plotted points are the mean (± SEM) for each mouse across all four feed days, with c.30 mosquitoes per feed. Diamonds, S alleles; squares, R alleles. (2 of 83 infections corresponding to either S or S+R alleles are not included).
Mentions: At the start of drug treatment, resistant parasites constituted less than 0.05% of the parasite and gametocyte populations. After treatment, the population of resistant parasites rapidly expanded (Figure 1– bottom panel, Figure 2– panels G–L), so that the resistant clone became the numerically dominant two days after the cessation of drug treatment (day 11 PI). A day later, the resistant clone made up more than 95% of the parasite population (Figure 3). Drug treatment completely cleared susceptible parasites in only two of the six mice used for mosquito blood feeds (Figure 2– panels I & L). In the other four mice, susceptible parasites were undetectable for 2 to 8 days before they recrudesced to varying degrees (Figure 2– panels G, H, J & K).

Bottom Line: Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it.We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes.Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

ABSTRACT
The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

Show MeSH
Related in: MedlinePlus