Abstract
The best correlate of malaria severity in human Plasmodium falciparum (Pf) infection is the total parasite load. Pf-infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo. Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients, and tracked the fate of donor parasites by frequent blood sampling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.
Highlights
Reduced erythrocyte susceptibility and increased host clearance of young parasites slows Plasmodium growth in a murine model of severe malaria
Parasite multiplication rate is reduced in Plasmodium berghei ANKA (PbA) infection
Our previous work suggested that parasite multiplication rates (PMRs) in the bloodstream drops over the course of acute PbA infection in mice, direct measures of this were not made[14]
Summary
Reduced erythrocyte susceptibility and increased host clearance of young parasites slows Plasmodium growth in a murine model of severe malaria. Experimental models of blood-stage malaria have been used extensively to identify host immunological and pathological mechanisms that may operate in humans[5,6,7,8,9] One such model is the infection of inbred C57BL/6 mice with the rodent infective parasite, Plasmodium berghei ANKA (PbA). We hypothesized here that early control of parasite multiplication in the blood-stream in this model is mediated predominantly by active clearance of infected RBC from peripheral circulation To test this in vivo, we developed novel methods for directly measuring host-mediated clearance of parasites from circulation. Using this approach, we demonstrated, firstly, that parasite multiplication rates dropped substantially during infection, and secondly, that parasite clearance increased during early PbA infection, as the host acquired the capacity to clear parasites at earlier developmental stages. An accompanying phenomenon of altered RBC susceptibility, in which uninfected RBCs within an infected host became refractory to infection, acts to slow parasite multiplication during infection
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