Abstract
Many questions remain about P. falciparum within-host dynamics, immunity, and transmission–issues that may affect public health campaign planning. These gaps in knowledge concern the distribution of durations of malaria infections, determination of peak parasitemia during acute infection, the relationships among gametocytes and immune responses and infectiousness to mosquitoes, and the effect of antigenic structure on reinfection outcomes. The present model of intra-host dynamics of P. falciparum implements detailed representations of parasite and immune dynamics, with structures based on minimal extrapolations from first-principles biology in its foundations. The model is designed to quickly and readily accommodate gains in mechanistic understanding and to evaluate effects of alternative biological hypothesis through in silico experiments. Simulations follow the parasite from the liver-stage through the detailed asexual cycle to clearance while tracking gametocyte populations. The modeled immune system includes innate inflammatory and specific antibody responses to a repertoire of antigens. The mechanistic focus provides clear explanations for the structure of the distribution of infection durations through the interaction of antigenic variation and innate and adaptive immunity. Infectiousness to mosquitoes appears to be determined not only by the density of gametocytes but also by the level of inflammatory cytokines, which harmonizes an extensive series of study results. Finally, pre-existing immunity can either decrease or increase the duration of infections upon reinfection, depending on the degree of overlap in antigenic repertoires and the strength of the pre-existing immunity.
Highlights
Mathematical modeling of malaria necessarily includes more than population-level transmission models [1,2,3,4,5] and extends to detailed models of within-host dynamics [6,7,8,9,10]
This paper presents a novel mechanistic intrahost model and model-based simulations of the dynamics of P. falciparum
Analysis of the Malariatherapy Dataset Malariatherapy data provide much of the current understanding of the course of blood-stage P. falciparum in an immunologically naıve individual [26]
Summary
Mathematical modeling of malaria necessarily includes more than population-level transmission models [1,2,3,4,5] and extends to detailed models of within-host dynamics [6,7,8,9,10]. Crucial questions about malaria infections–including those regarding the duration of patent parasitemia [11] and the extent of subpatent and asymptomatic infections in a partially-immune population [1,10]–can be studied and explored within a suitably detailed intrahost model. These detailed models can be used to explore and to understand relationships among gametocytes, immunity, and human infectiousness to mosquitoes [12]. Intrahost models can be used to evaluate hypotheses regarding parasite within-host dynamics and immune responses and to propose new experiments and field studies
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