Dissecting the complexity of human susceptibility to Plasmodium falciparum malaria: genetic approaches

Abstract: There are many aspects of the immunology of P. falciparum infection that are not understood. Genetic approaches are of great value for dissecting the complexity of immune responses to malaria in natura by providing new insights into molecular interactions between the parasite and the host. The work presented in this thesis had two major aims: to investigate the role of IFN-γ signalling in susceptibility to malaria; and to understand the biological basis of the low susceptibility to malaria shown by the Fula people of West Africa. We conducted genetic association studies to investigate the role of four candidate loci: IFNG, IFNGR1, IFNGR2 and IRF1. We observed significant associations between common genetic variation at the IRF1 locus and the ability to control P. falciparum infection. Our studies did not provide evidence for a major role of this gene in determining susceptibility to severe malaria. Using allele-specific expression assays we obtained preliminary results suggesting the existence of a regulatory element(s) in the 5’ upstream region of the IRF1 locus. IRF1 polymorphisms regulating gene expression could affect the production of inflammatory cytokines and the control of infection, but not the immune-based pathogenesis of severe disease. To understand the biological basis of the resistance to malaria shown by the Fula, we analysed HLA class II polymorphism and confirmed previous data showing that the Fula from Burkina Faso are genetically distinct from sympatric Mossi and Rimaibé. We then compared the expression profiles of PBMCs and CD4+CD25+ cells isolated from healthy adults of Fula and Mossi ethnicity. In the Fula we observed higher expression of several genes related to Th1 and Th2 function and reduced expression of important genes related to immune tolerance: FOXP3, CTLA4, TGFB and TGFBRs. These results suggest a functional deficit of T regulatory cells in the Fula and identify key genes as good candidates for future genetic association studies.