Modelling the effects of chemotherapy on the within-host dynamics of human malaria infection and immune response

Saralamba, Sompob (2015). Modelling the effects of chemotherapy on the within-host dynamics of human malaria infection and immune response. PhD thesis The Open University.



Host immunity and parasite stage specific sensitivity and resistance to antimalarial drugs are important determinants of the natural course of Plasmodium falciparum infections and the therapeutic response to antimalarial drugs. The relationship between these factors is incompletely understood. In this thesis, a series of discrete time mathematical models were developed to study the dynamics of P. falciparum parasites in malaria infected patients. The models were used to test two main hypotheses: 1) Host immunity regulates parasite load and can explain the plateauing of asexual stage parasitaemia observed during natural infection; 2) Deceleration of parasite clearance following artesunate treatment in patients infected with artemisinin resistant P. falciparum results from reduced drug eficacy against the ring stage of the asexual parasite lifecycle. To test the first hypothesis, detailed historical data from the era of malaria therapy for neurosyphilis were used. The model output predicted that increased peripheral blood parasite density was positively correlated with and resulted in an increase in host immunity over time. This host immunity subsequently contains the infection resulting in a sharp reduction in the parasite multiplication rate. This mathematical model was then adapted to examine the second hypothesis using data from detailed parasite clearance studies in patients treated with artesunate in Western Cambodia, an area of artemisinin resistance. The model output clearly supported that loss of ring stage sensitivity was the main factor explaining the overall deceleration in parasite clearance after artesunate treatment. This result prompted the development of ring-stage specific in-vitro artemisinin sensitivity tests, which further confirmed the hypothesis. Remaining questions include: whether gametocytogenesis can also explain the plateauing of parasitaemia and whether the level of splenic pitting is correlated with artemisinin resistance. To address this, future extensions of the model will include additional parasite life cycle stages, including sexual stages, as well as the interactions between parasites, erythrocytes and the spleen.

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