Defining the immunological basis of cerebral pathology during murine experimental cerebral malaria and understanding the basis of infection induced resistance

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Abstract

Malaria affects 200 million people annually, resulting in 584,000 – 1,238,000 deaths. The majority of these deaths occur in children, less than 5 years of age, in sub-Saharan Africa and are due to cerebral malaria (CM), a neuropathology induced primarily by the species Plasmodium (P.) falciparum. The pathogenesis of CM remains poorly understood and the mechanisms involved in acquired protection against the syndrome in malaria-endemic regions are undefined.Utilising the well characterised P. berghei ANKA experimental infection model of cerebral malaria (ECM), results presented in this thesis show that the development of ECM is associated with the accumulation and arrest of pathogenic CD8+ T cells within the perivascular spaces of the brain. Accumulation of activated CD8+ T cells, without arrest, was observed in the perivascular spaces of the brains of mice infected with the non-ECM causing P. berghei NK65 strain. These data show that the behaviour of intracerebral CD8+ T cells specifies their pathogenic function during malaria infection. The development of ECM was associated with extensive disruption to the BBB, which developed in the absence of extensive CD8+ T cell-dependent endothelial cell apoptosis. We modified the ECM model, establishing an infection-drug cure strategy, to investigate the immunological basis of parasite exposure-induced resistance to ECM development. Three rounds of infection-drug cure promoted resistance to ECM, which was associated with reduced intracerebral expression of genes involved in defence response, regulation of apoptosis, chemotaxis, CTL activity, antigen processing and presentation and cell adhesion, compared with ECM susceptible mice. Additionally, CD8+ T cell activation was suppressed in exposure-induced resistant mice and was associated with the antibody dependent expansion of a splenic plasmacytoid DC population, with a regulatory phenotype. The infection-induced protection against ECM was critically dependent upon secreted antibody production.A long standing problem in studying the immune response to malaria infection has been the inability to track parasite-specific CD4+ T cell responses. To address this, we generated and validated new transgenic P. berghei parasites expressing the model antigen, ovalbumin (OVA), either in the parasite cytoplasm or on the parasitophorous vacuole membrane (PVM). We found that cellular location and expression level of the antigen influence the induction and magnitude of parasite-specific T-cell responses. These parasites thus provide knowledge on the factors that influence the recognition of parasite antigens by the immune system and represent useful tools to study the development and function of antigen-specific T-cell responses during malaria infection.The results in this thesis improve our understanding of the events that lead to the development of CM, and the host immune responses that develop following parasite exposure to protect against it. The results should contribute towards the rational development of adjunctive therapies and effective vaccines for human CM.

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List of supplementary movies on compact disc submitted in pocket inside back cover of print version of thesis: -Supplementary Video 2.1. Transient cytoadhesion of intravascular Pb ANKA-pRBCsSupplementary Video 2.2. Occurrence of perivascular pRBCsSupplementary Video 2.3. Infection with LCMV induces petechial hemorrhagesSupplementary Video 2.4. Perivascular location and arrested behavior of T cells during Pb ANKA infectionSupplementary Video 2.5. Perivascular location and dynamic behavior of T cells during Pb NK65 infectionSupplementary Video 2.6. Perivascular DsRed T cells form stable interactions with CX3CR1+/GFP cells in the brains of mice infected with Pb ANKASupplementary Video 2.7. Perivascular DsRed T cells make contact, but do not form stable interactions, with CX3CR1+/GFP cells in the brains of mice infected with Pb NK65Supplementary Video 2.8. Perivascular DsRed T cells form stable interactions with CX3CR1+/GFP cells in the brains of mice infected with Pb ANKASupplementary Video 2.9. Perivascular DsRed antigen-specific T cells are mostly arrested in the brains of mice infected with Pb ANKA

Keyword(s)

CD8+ T cell; Cerebral malaria; Intravital imaging; Malaria; Multiphoton

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