Malaria is a deadly disease caused by the protozoan parasite Plasmodium spp., which displays a complex intrahost lifecycle. Most within-host parasite proliferation involves the continuous infection of red blood cells (RBCs) by the asexual stage. However, a small proportion of parasites produces a sexual stage transmissible to mosquitos. The proportion of sexually-committed parasites is termed the “conversion rate” and is phenotypically plastic, changing over time and responding to within-host environments. Since the conversion rate affects infectiousness and disease severity, there is a strong interest in understanding the factors that influence conversion rate evolution. To date, most mathematical models exploring conversion rate have assumed that parasites have perfect knowledge of infection progression by treating conversion rate as a function of time. Although this is mathematically convenient, it is biologically naive. Here, we present a mathematical model that describes the intrahost dynamics of the rodent malaria parasite Plasmodium chabaudi and allows the conversion rate to depend on environmental cues. With this model, we explored the effects of different cue usage on parasite fitness and host condition. The reliability of different cues in the face of biological noise is determined by incorporating environmental and demographic stochasticity into the modelling process.
Results/Conclusions:
We show that cue choice and perception affect parasite fitness. The optimal cue is often a proxy for parasite density, which coupled with a right-skewed unimodal reaction norm, allows parasites to initially delay transmission investment before rapidly increasing their conversion rate when the parasite population expands. This conversion rate dynamic allows the parasite to achieve two goals; the rapid increase in conversion rate maintains sufficient gametocyte density that ensures between-host transmission; the high conversion rate also limits total parasite density, decreasing immunity activation. Aside from mediating parasite response, we also show that the choice of cues influences parasite fitness under environmental and demographic stochasticity. We find that variations in parasite burst size (the number of progenies per infected red blood cell (iRBC)) exert the most influence on parasite fitness across all cues. We also demonstrate that parasite-centric cues are more sensitive to fluctuations in targeted immunity that eliminates iRBC. In contrast, host-centric cues, such as RBC density, are more sensitive to fluctuations in indiscriminate immunity that eliminates both RBC and iRBC. Overall, the data show that different cue usage significantly impacts malaria intrahost dynamics, affirming the critical role that conversion rate plays in Plasmodium biology.
