Malaria remains one of the world's major health problems, especially in developing countries. A better understanding of the pathology and pathophysiology of severe malaria is key to develop new treatments. Different approaches have been used in malaria research including the in vitro co-culture models with endothelial cells and both murine and simian animal models. However these are open to controversy due to disagreement on their representativeness of human disease. Using human post-mortem tissue in malaria research is another important approach but is practically challenging, limiting the availability of post mortem samples from malaria patients. The work in this thesis had two main themes. First I examined the role of the endothelial signalling Angiopoetin-Tie-2 receptor pathway in malaria. Ang-2 has been shown to be a significant biomarker of severe and fatal malaria. I examined the tissue specific expression of proteins from this pathway in post-mortem brain tissues from fatal malaria cases, but found no difference between cerebral malaria and non-cerebral malaria cases. Ang-2 correlated with the severity of malaria in these patients. An attempt to examine the interaction of hypoxia and the Ang-Tie-2 pathway in vitro using a co-culture model of human brain endothelial cells was unsuccessful due to contamination of the cell line. The second part of the thesis aimed to utilise molecular pathology techniques including miRNA and whole-genome microarrays. I have shown for the first time that these can be successfully applied to human post-mortem tissue in malaria. First I used archival tissues to examine the microRNA signature in the kidney of patients with malaria associated renal failure. Second I optimised a protocol to preserve post mortem tissue for molecular pathology, from an autopsy study in Mozambique. Using the subsequent total mRNA transcriptomic data and bioinformatics analysis this work has expanded our knowledge of differential gene expression and the families of genes which are dysregulated in the brain in response to malaria infection.

La mucoviscidose est une pathologie pulmonaire causée par un dysfonctionnement du canal CFTR et caractérisée par un mucus visqueux, une susceptibilité accrue aux infections chroniques et une inflammation excessive. Une première partie de ma thèse a eu pour objectif d’étudier les mécanismes inflammatoires impliqués dans le développement de la pathologie. Nous avons plus particulièrement analysé le rôle de l’IL-1β et de l’IL-17 dans la réponse à l’infection par Pseudomonas aeruginosa, dans le modèle murin ΔF508 de mucoviscidose. La seconde partie de ma thèse a porté sur l’étude de la malaria pulmonaire et cérébrale, une complication létale de l’infection à P. falciparum. Nous avons mis en évidence l’importance de trois voies d’activation des lymphocytes T CD8+ cytotoxiques dans le développement de la neuropathologie induite par Plasmodium berghei ANKA chez la souris : la protéine PKC-θ, la sous-unité β2 du récepteur à l’IL-12 et le récepteur des IFN de type I, mais qui ne semblent pas impliquées dans l’inflammation pulmonaire associée. / Cystic fibrosis is a pulmonary pathology, caused by the CFTR channel dysfunction, and characterized by high mucus viscosity, increased sensitivity to chronic infections and excessive inflammation. The aim of my thesis was first to study the inflammatory mechanisms involved in this lung pathology. Indeed, we analyzed the role of IL-1β and IL-17 in response to Pseudomonas aeruginosa infection, in the ΔF508 mouse model of cystic fibrosis. In the second part of my thesis, I studied pulmonary and cerebral malaria, a lethal complication of P. falciparum infection. We showed the importance of three pathways implicated in cytotoxic CD8+ T lymphocytes activation during the Plasmodium berghei ANKA-induced neuropathology development in mice: PKC-θ protein, β2 subunit of IL-12 receptor and type I IFN receptor, which did not seem essential for the associated lung inflammation.