Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2–3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems.
Malaria is a disease caused by a protozoan parasite of the genus Plasmodium. Every year there are around 250 million human cases of malaria, resulting in around a million deaths. Most of the severe cases and deaths are due to Plasmodium falciparum, which is endemic in much of sub-Saharan Africa and other tropical areas. The pathology of malaria is related to the asexual stage of the parasite. Understanding the infection dynamics during this stage is therefore essential to inform malaria treatment and vaccine design. Experimental infections of rodents represent an important first step towards understanding the more complicated human infections. We developed a series of models representing different hypotheses about the main processes regulating the infection dynamics during the asexual stage. Models were fit to data on Plasmodium chabaudi infections of mice, using a Bayesian statistical framework. The accuracy of different models in explaining the RBC and parasite densities was quantified. We identify the role of different types of immune-mediated mechanism, and show that RBC production (erythropoiesis) increases during infection. Differences between mouse phenotypes are explained. Our study highlights the informative power of model-fitting techniques in explaining biological systems.