Mathematical modelling of the dynamics of malaria infection

In this thesis I investigate several important aspects of natural mechanisms of resistance against malaria infection that are poorly understood but have important implications for control and prevention of malaria-associated disease.The thesis starts with an analysis of field data from a cohort of patients from a malaria endemic area. The cohort of patients included children of varying ages and adults. I firstly used a modelling approach to understand how resistance to malaria is acquired with age and prolonged exposure. I compared the impact of the two major postulated mechanisms of resistance, immunity to either liver stage or blood stage parasites. I used a modelling approach to understand what type of immunity could reproduce the observed dynamics of infection for the different age groups. I found that the reinfection pattern could be completely explained by blood stage immunity. Moreover, the blood stage immunity must consist of rapidly induced strain-specific immunity, and general immunity that accumulates slowly and decreases the average parasite growth rate with age.Further analysis of the same cohort aimed to investigate whether the high blood-stage parasitaemia levels seen in children may inhibit the development of subsequent liver stage infections in humans as has recently been shown in a mouse model. My statistical analysis of ‘natural infection’ field data and stochastic simulation of infection dynamics show that the data is consistent with high P. falciparum parasitaemia inhibiting liver stage parasite development in humans.The goal of the final chapter of my Thesis is to understand the mechanisms that lead to increased clearance of uninfected red blood cells during malaria infection. It has previously been observed that there is a high level of ‘bystander destruction’ of uninfected RBC, and that this may be a major reason for anaemia. For this purpose, mathematical methods were applied to experimental data, where red blood cells were adoptively transfused between infected and uninfected mice. My mathematical modelling aimed to dissect the level of intrinsic RBC damage, and its mechanisms. The results suggest accelerated senescence of RBC is induced by infection, most likely as a result of an activated spleen. Together this work provides a number of novel insights into the infection biology of malaria infection in vivo