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- Mangano, Valentina D, 1980-
(författare)
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Dissecting the complexity of human susceptibility to Plasmodium falciparum malaria: genetic approaches
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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- Mangano, Valentina D, et al.
(författare)
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Lack of association of Interferon Regulatory Factor 1 with severe malaria in affected child‐parental trio studies across three African populations
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:1, s. e4206-
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Tidskriftsartikel (refereegranskat)abstract
- Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.
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- Shelton, Jennifer M. G., et al.
(författare)
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Genetic determinants of anti-malarial acquired immunity in a large multi-centre study
- 2015
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP) 4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)(4) epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.
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