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

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

doi:10.1098/rspb.2012.1792

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.

Highlights

Radical alterations in parasite ecology such as that imposed by drug treatment can exert selective effects on the life-history traits and behaviours of parasites [1,2,3,4,5]
We present a series of experiments asking the following questions: does virulence reduce sensitivity to different treatment regimens of artemisinin, an antimalarial drug which kills transmission stages as well as asexual stages [22] and is currently the frontline drug of choice in much of the world [23]? Does the survival advantage hold when parasites are competing in genetically diverse infections? What are the transmission consequences of virulence in pyrimethamine- and in artemisinin-treated infections? Our data reveal that virulence enhances in-host survival in single and mixed infections treated with either pyrimethamine or artemisinin, and when exposed to drugs, host-to-vector transmission is enhanced for virulent parasites, an advantage that is minimized by treatment with artemisinin
We carried out four experiments to compare the effects of drug treatment on the survival and transmission of two P. chabaudi genotypes that differ in virulence

Summary

INTRODUCTION

Radical alterations in parasite ecology such as that imposed by drug treatment can exert selective effects on the life-history traits and behaviours of parasites [1,2,3,4,5]. Traits that govern the growth and reproductive patterns of parasites can influence their survival and transmission in drug-treated infections [6,7,8,9,10,11,12,13,14,15,16,17,18] These life-history traits need not involve direct intracellular interactions with drug molecules, yet can reduce sensitivity to treatment. Activity during exposure [9,10,11,18], and faster replication rates in malaria parasites and worms that may provide protection through safety in numbers or by minimizing the period when a vulnerable life-cycle stage is exposed to drugs [12,15] These life-history traits can underpin both virulence and transmission [12,19 – 21].

CWvir placebo

RESULTS

AVIR VIR dose

DISCUSSION

CWvir ART

CWavir CWvir