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Dissecting the complexity of human susceptibility to Plasmodium falciparum malaria: genetic approaches
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2008. , 124 p.
Keyword [en]
immunology, genetics, malaria
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-8310ISBN: 978-91-7155-713-1 (print)OAI: oai:DiVA.org:su-8310DiVA: diva2:200063
Public defence
2008-12-03, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 8 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-11-12 Created: 2008-11-06Bibliographically approved
List of papers
1. Interferon Regulatory Factor 1 polymorphisms are associated with the control of Plasmodium falciparum infection
Open this publication in new window or tab >>Interferon Regulatory Factor 1 polymorphisms are associated with the control of Plasmodium falciparum infection
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2008 In: Genes and Immunity, ISSN 1466-4879, Vol. 9, no 2, 122-129 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25617 (URN)
Note
Part of urn:nbn:se:su:diva-8310Available from: 2008-11-12 Created: 2008-11-06Bibliographically approved
2. Lack of association of Interferon Regulatory Factor 1 with severe malaria in affected child‐parental trio studies across three African populations
Open this publication in new window or tab >>Lack of association of Interferon Regulatory Factor 1 with severe malaria in affected child‐parental trio studies across three African populations
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2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 1, e4206- p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:su:diva-25618 (URN)10.1371/journal.pone.0004206 (DOI)
Note
Part of urn:nbn:se:su:diva-8310Available from: 2008-11-12 Created: 2008-11-06 Last updated: 2010-01-17Bibliographically approved
3. HLA class II loci polymorphism in three West African ethnic groups showing different immune response to Plasmodium falciparum malaria.
Open this publication in new window or tab >>HLA class II loci polymorphism in three West African ethnic groups showing different immune response to Plasmodium falciparum malaria.
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Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25619 (URN)
Note
Part of urn:nbn:se:su:diva-8310Available from: 2008-11-12 Created: 2008-11-06 Last updated: 2010-01-13Bibliographically approved
4. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria
Open this publication in new window or tab >>Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria
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2008 In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, Vol. 105, no 2, 646-651 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25620 (URN)
Note
Part of urn:nbn:se:su:diva-8310Available from: 2008-11-12 Created: 2008-11-06Bibliographically approved

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