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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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Relationship between gametocyte densities in mice at the time of a blood feed and the subsequent prevalence of infection in mosquitoes fed on those mice for untreated infections with transmission of clone S (red points) and for drug-treated infections with transmission of clone R (black points).The thick red and black lines show the predicted probability of mosquito infection based on logistic regression (eq 1), and the shaded areas show the 90% prediction intervals (note that these are not confidence intervals, see text for details). Two oocysts consisting of clone S were observed in drug treated infections (open red triangles), these were not included in the model (see text). Blue lines are gametocyte density-infectivity functions (of the form q = αNβ/[1+ γNβ]) estimated from P. falciparum data compiled by Carter and Graves [66] and Barnes & White [67]: q1 (dot-dashed blue line;α = 0.03, β = 0.6, α/γ = 0.85) and q2 (solid blue line; α = 1·10−5, β = 2, α/γ = 1) as presented by Huijben et al. [34].
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pone-0037172-g005: Relationship between gametocyte densities in mice at the time of a blood feed and the subsequent prevalence of infection in mosquitoes fed on those mice for untreated infections with transmission of clone S (red points) and for drug-treated infections with transmission of clone R (black points).The thick red and black lines show the predicted probability of mosquito infection based on logistic regression (eq 1), and the shaded areas show the 90% prediction intervals (note that these are not confidence intervals, see text for details). Two oocysts consisting of clone S were observed in drug treated infections (open red triangles), these were not included in the model (see text). Blue lines are gametocyte density-infectivity functions (of the form q = αNβ/[1+ γNβ]) estimated from P. falciparum data compiled by Carter and Graves [66] and Barnes & White [67]: q1 (dot-dashed blue line;α = 0.03, β = 0.6, α/γ = 0.85) and q2 (solid blue line; α = 1·10−5, β = 2, α/γ = 1) as presented by Huijben et al. [34].

Mentions: In the absence of drug treatment, only clone S was transmitted to mosquitoes. Successful formation of oocysts was observed only when gametocyte densities exceeded 102.5/µl of mouse blood (Figure 5). Prevalence of infection rose sharply with increasing gametocyte densities, withevery mouse exceeding this threshold infectious to mosquitoes. Following drug treatment, successful transmission was almostentirely due to resistant parasites, although one mosquito harboured a single oocyst with just the clone S genotype (Figure 2– panel G) and another mosquito bore an oocyst that had apparently resulted from cross-fertilization (contained both clone genotypes; Figure 2– panel J). Transmission of the resistant clone after drug treatment occasionally occurred at lower gametocyte densities than was observed for sensitive clone transmission, but also sometimes failed at densities greater than 103.5 per micro-liter mouse blood (Figure 5). Interestingly, the two oocysts with clone S alleles that established from drug-treated mice did so when densities of sensitive gametocytes in the blood were lower than apparently necessary for transmission in the absence of drug treatment (Figure 5).


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)

Relationship between gametocyte densities in mice at the time of a blood feed and the subsequent prevalence of infection in mosquitoes fed on those mice for untreated infections with transmission of clone S (red points) and for drug-treated infections with transmission of clone R (black points).The thick red and black lines show the predicted probability of mosquito infection based on logistic regression (eq 1), and the shaded areas show the 90% prediction intervals (note that these are not confidence intervals, see text for details). Two oocysts consisting of clone S were observed in drug treated infections (open red triangles), these were not included in the model (see text). Blue lines are gametocyte density-infectivity functions (of the form q = αNβ/[1+ γNβ]) estimated from P. falciparum data compiled by Carter and Graves [66] and Barnes & White [67]: q1 (dot-dashed blue line;α = 0.03, β = 0.6, α/γ = 0.85) and q2 (solid blue line; α = 1·10−5, β = 2, α/γ = 1) as presented by Huijben et al. [34].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368907&req=5

pone-0037172-g005: Relationship between gametocyte densities in mice at the time of a blood feed and the subsequent prevalence of infection in mosquitoes fed on those mice for untreated infections with transmission of clone S (red points) and for drug-treated infections with transmission of clone R (black points).The thick red and black lines show the predicted probability of mosquito infection based on logistic regression (eq 1), and the shaded areas show the 90% prediction intervals (note that these are not confidence intervals, see text for details). Two oocysts consisting of clone S were observed in drug treated infections (open red triangles), these were not included in the model (see text). Blue lines are gametocyte density-infectivity functions (of the form q = αNβ/[1+ γNβ]) estimated from P. falciparum data compiled by Carter and Graves [66] and Barnes & White [67]: q1 (dot-dashed blue line;α = 0.03, β = 0.6, α/γ = 0.85) and q2 (solid blue line; α = 1·10−5, β = 2, α/γ = 1) as presented by Huijben et al. [34].
Mentions: In the absence of drug treatment, only clone S was transmitted to mosquitoes. Successful formation of oocysts was observed only when gametocyte densities exceeded 102.5/µl of mouse blood (Figure 5). Prevalence of infection rose sharply with increasing gametocyte densities, withevery mouse exceeding this threshold infectious to mosquitoes. Following drug treatment, successful transmission was almostentirely due to resistant parasites, although one mosquito harboured a single oocyst with just the clone S genotype (Figure 2– panel G) and another mosquito bore an oocyst that had apparently resulted from cross-fertilization (contained both clone genotypes; Figure 2– panel J). Transmission of the resistant clone after drug treatment occasionally occurred at lower gametocyte densities than was observed for sensitive clone transmission, but also sometimes failed at densities greater than 103.5 per micro-liter mouse blood (Figure 5). Interestingly, the two oocysts with clone S alleles that established from drug-treated mice did so when densities of sensitive gametocytes in the blood were lower than apparently necessary for transmission in the absence of drug treatment (Figure 5).

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