Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy

Abstract

SUMMARYBoth theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.

Life history of a malaria parasite (Plasmodium mexicanum): independent traits and basis for variation

“…As conditions become unsuitable for further asexual growth, the parasite switches to the only stages which can leave the host, the gametocytes. The proximate cues used by the parasite can include the host's immune response (Cornelissen & Walliker 1985), the production of stress hormone by the host (Maswoswe et al 1985) and even novel chemical stressors presented by various anti-malarial drugs (Buckling et al 1997(Buckling et al , 1999Butcher 1997). The mechanism used by the parasite in detecting such a broad array of signals and then altering its development to produce gametocytes is unknown (Sinden 1983;Carter & Graves 1988), but the very fact that Plasmodium species have evolved a suite of transduction pathways illustrates the importance of plasticity in this life-history trait.…”

“…Alternatively, clonal diversity in infections could itself alter the behaviour of each clone . A minority view, although a venerable one (Thomson 1911;Boyd 1939), holds that variation between infections re£ects adaptive phenotypic plasticity, such as a switch to gametocyte production when the host environment deteriorates (Buckling et al 1997(Buckling et al , 1999.…”

Biology of Malaria Transmission

“…Total parasite density in an individual can influence gametocytogenesis as a relatively higher concentration of gametocytes was observed in individuals with low-density infections when compared with those with high-density infections . Evidence from clinical observations during human or experimental infections suggests an increased gametocyte production following drug treatment (Buckling et al 1997;Price et al 1999;Bousema et al 2003;Sowunmi et al 2011), indicating that inefficient treatment and/or parasite recrudescence are associated with higher gametocyte numbers (Price et al 1999;Barnes et al 2008). These studies suggest that selection of drug-resistant parasite clones may be associated with increased chances of transmission; however, this hypothesis has yet to be systematically tested given the complex relationship between drug resistance and malaria transmission, which involves factors such as multiplicity of resistant clones, transmission intensity, and the genetic nature of resistance traits (Talisuna et al 2003).…”

The potential impact of integrated malaria transmission control on entomologic inoculation rate in highly endemic areas.

“…11,21 What is not clear is whether wide-scale chemoprophylaxis reduces or increases the infectiousness of the human reservoir in endemic areas. [22][23][24][25] Even if the infectiousness of the human reservoir can be reduced, it is difficult to justify the use of antimalarial drugs for transmission control. This is because the widespread administration of drugs is not only expensive and difficult to implement, but also promotes resistance in the parasite population and makes life-threatening cases more difficult to treat.…”