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. 2012 Nov 22;279(1747):4677-85.
doi: 10.1098/rspb.2012.1792. Epub 2012 Sep 26.

Virulence, drug sensitivity and transmission success in the rodent malaria, Plasmodium chabaudi

Petra Schneider  1 , Andrew S Bell, Derek G Sim, Aidan J O'Donnell, Simon Blanford, Krijn P Paaijmans, Andrew F Read, Sarah E Reece
Affiliations

Virulence, drug sensitivity and transmission success in the rodent malaria, Plasmodium chabaudi

Petra Schneider et al. Proc Biol Sci. .

Abstract

Here, we test the hypothesis that virulent malaria parasites are less susceptible to drug treatment than less virulent parasites. If true, drug treatment might promote the evolution of more virulent parasites (defined here as those doing more harm to hosts). Drug-resistance mechanisms that protect parasites through interactions with drug molecules at the sub-cellular level are well known. However, parasite phenotypes associated with virulence might also help parasites survive in the presence of drugs. For example, rapidly replicating parasites might be better able to recover in the host if drug treatment fails to eliminate parasites. We quantified the effects of drug treatment on the in-host survival and between-host transmission of rodent malaria (Plasmodium chabaudi) parasites which differed in virulence and had never been previously exposed to drugs. In all our treatment regimens and in single- and mixed-genotype infections, virulent parasites were less sensitive to pyrimethamine and artemisinin, the two antimalarial drugs we tested. Virulent parasites also achieved disproportionately greater transmission when exposed to pyrimethamine. Overall, our data suggest that drug treatment can select for more virulent parasites. Drugs targeting transmission stages (such as artemisinin) may minimize the evolutionary advantage of virulence in drug-treated infections.

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Figures

Figure 1.
Figure 1.
Drug sensitivity of virulent and avirulent parasite genotypes. Virulent (black squares, CWvir) asexual parasites are less sensitive to artemisinin treatment than avirulent (grey circles, CWavir) parasites in all dose and duration regimens tested. Infections were treated with placebo (0) or artemisinin at doses of 50, 100, 150 or 200 mg kg mouse−1. Data presented are model predictions from experiments 1–3 (mean and s.e. of cumulative asexual parasite densities from day 6–21 after infection) from GLMs controlling for weight and RBC density at the day of infection and asexual parasite density at time of treatment. Note that doses 0 (Navir = 14, Nvir = 14), 50 (Navir = 15, Nvir = 15) and 100 (Navir = 13, Nvir = 15) were used in all three experiments, but doses 150 (Navir = 5, Nvir = 5) and 200 (Navir = 5, Nvir = 4) were only used in, respectively, experiments 1 and 2.
Figure 2.
Figure 2.
Transmission success in mixed-genotype infections. In mixed infections with a common competitor (DK), virulent (CWvir) parasites have a transmission (fitness) advantage over avirulent (CWavir) parasites, which is enhanced by treatment with pyrimethamine. Transmission success is presented as the mean ± s.e. of the proportion of CW alleles, relative to DK alleles, within infected mosquitoes. Treatment groups with sample sizes (number of feeds resulting in infected mosquitoes for avirulent and virulent CW genotypes) were: Placebo: no drugs (Navir = 5, Nvir = 3); PYR: pyrimethamine at 1 or 3 mg kg−1 (Navir = 8, Nvir = 7); ART: artemisinin at 50 or 100 mg kg−1 (Navir = 8, Nvir = 8) and feeds were carried out on days 7, 11, 15 and 19 post infection.
Figure 3.
Figure 3.
Correlation between gametocyte density, representation in the gametocyte pool and mosquito infections. The density of gametocytes (gcts) for avirulent (grey circles, CWavir) and virulent (black circles, CWvir) parasites in mixed genotype infections with common competitor, DK, correlates positively with representation in the gametocyte pool and in mosquitoes. (a) For a given gametocyte density, CWvir (r2 = 0.31, p = 0.02) gains greater representation in the gametocyte pool than CWavir (r2 = 0.39, p < 0.001). (b) The proportion of CW gametocytes correlates positively with the frequency of the CW allele within infected mosquitoes (r2 = 0.85, p < 0.001; for both genotypes). Put simply, because CWvir achieves greater representation than CWavir in the gametocyte pool, it gains greater representation in infected mosquitoes. Data are presented for all treatment groups ((a) experiment 4 and experiment 3 on days of mosquito feeds only, Nvir = 127, Navir = 132; (b) experiment 4 Nvir = 18, Navir = 21).
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