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Abstract

Cerebral Malaria is a complex neurological condition that results from interaction between the host and the Plasmodium parasite through the different phases of parasite's life-cycle. This interaction ranges from infection to immune response triggered in the host system. Various strains of the Plasmodium parasites are found to have difference in the severity of disease after infection. However, the precise factors defining the infectivity of Plasmodium parasites and the resulting disease outcome have not been completely identified so far. In the thesis, the Plasmodium berghei mouse model for Malaria is used to characterize the infection dynamics of Plasmodium berghei ANKA (wild-type) and a mutant strain that lacks a Plasmodium antigen PbmaLS_05. The mutant infection leads to lower parasitemia in red blood cells and less severe disease outcome in contrast to mice infected with the wild-type strain. Moreover, the mice infected by injecting PbmaLS_05(-) KO-infected red blood cells show reduced immune response in contrast to infection with PbmaLS_05(-) KO-sporozoites. By developing mathematical models describing various mechanisms of the infection and fitting them to experimental data; I find factors that influence the difference in disease progression seen between the two strains. Most strikingly, the KO strain shows a decreased ability to infect immature red blood cells that are usually a preferred target of the parasite. This altered property of infection limits parasite burden and affects disease progression. In addition to this, a statistical analysis of immune activation and immune response data from the KO or WT infected mice was done, which resulted in selecting major indicators of cerebral Malaria. The analysis showed that the number of CD8+ T cells accumulated in the brain, the reduced proportion of CD8+ T cells to lymphocytes in the spleen, the increased presence of Malaria specific CD8+ IFN-+ T and the secondary activation of CD8+ T cells due to the antigens cross-presented by infected red blood cells sequestered in the brain are the prominent distinguishing factors between the ECM causing PbANKA and non-ECM causing PbmaLS_05 (-) infections. An exploratory analysis of the liver-stage of infection and immune response highlighted that PbmaLS_05 may not have an important role to play in triggered immune response during the liver-stage of Malaria. However, its absence may lead to a small decrease in number of productive infections during the liver-stage, which must be further investigated. The antigen PbmaLS_05 can potentially aid in discovering the factors that influence the activation of immune responses and that might contribute to vaccine development and efficient parasite control.