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Combinaison d’approches expérimentales et bioinformatiques pour caractériser les intéractions entre Plasmodium falciparum et son hôte humain

Abstract : The first part of my thesis deals with the experimental characterization of Plasmodium falciparum submicroscopic infections in asymptomatic Congolese women during childbirth. Malaria remains a major public health problem in the world with about 219 million cases and 435,000 deaths a year, mostly in sub-Saharan Africa (90%). In the area of high transmission, malaria infection is mainly characterized by the onset of maternal anemia and the presence of parasites in the placenta. A high proportion of individuals living in malaria-endemic areas harbor parasites undetectable by microscopy, but which can nevertheless be detected using molecular tools such as PCR. Morbidity and mortality related to gestational malaria has decreased since the introduction of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPT-SP). In the endemic area, there is a decrease in the prevalence of placental malaria and an increase in the average weight of the newborn. Nevertheless, the plasmodial infection in the pregnant woman persists and is not controlled. In order to understand the causes of this persistence, I characterized the parasitic populations of P. falciparum in Congolese pregnant women from southern Brazzaville on IPT-SPand I analyzed their genetic profile in the peripheral blood, placental blood and umbilical cord. The evaluation of the frequency of the plasmodial infection has shown that the treatment correlates with a decrease in the frequency of microscopic infections and an increase in the frequency of submicroscopic infections with a moderate genetic diversity of P. falciparum. Age, pregnancy, and doses of SP do not interfere with the multiplicity of infections that are similar in all three types of blood. These results contribute to the understanding of parasite dynamics in peripheral, placental and umbilical cord blood and circulating parasite population in Congo. The second part of my thesis involved the use of bioinformatic approaches to detect regulatory variants associated with susceptibility to severe malaria. Recent advances in sequencing technologies enable to identify an increasingly broad spectrum of variants in the human genome. However, the identification of regulatory variants associated with complex diseases remains a challenge, particularly for identifying functionally relevant variants in non-coding regions. We have developed a bioinformatic method to predict regulatory variants of noncoding regions associated with a disease and acting on transcriptional regulation. The approach is based on the integration of various elements of information col- lected automatically from Ensembl database, dbSNP and GWAS catalog, and on the selection of variations that may affect regulation, by combining specialized bioinformatics tools: analysis Regulatory Sequence Analysis Tools and ChIP-seq (ReMap) data. To do this, we developed an analysis workflow in the R statistics language, which invokes remote resources (Web services). The tool is designed generically and can be adapted for the study of regulatory variants of any disease documented in the GWAS catalog. In order to facilitate its use by a biologist, the tool automatically generates (in R markdown) an analysis report illustrated by figures and tables. I tested the tool with an example case of severe malaria that showed that on a set of 375 candidate variants, the tool predicts eleven potential regulatory variants that alter the binding sites of transcription factors. Three of these candidate variants (rs1541253, rs1541254, rs1541255) associated with the ATP2B4 gene (plasma membrane calcium-transporting ATPase 4, encodes the main calcium pump of erythrocytes) are being experimentally validated for their impact on promoter activity.
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Yvon Mbouamboua. Combinaison d’approches expérimentales et bioinformatiques pour caractériser les intéractions entre Plasmodium falciparum et son hôte humain. Bio-informatique [q-bio.QM]. Aix-Marseile Université; Université Marien-Ngouabi (Brazzaville), 2019. Français. ⟨tel-02485381⟩

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