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Identification et caractérisation des facteurs cellulaires requis pour l’infection du virus Zika et du virus de la Dengue

Abstract : Dengue virus (DENV) and Zika virus (ZIKV) are two emerging viruses transmitted to humans by mosquitoes and are responsible for severe pathologies. There is currently no efficient vaccine neither antiviral treatment available against these arboviruses. DENV and ZIKV are fully dependent on the host cell for their multiplication. This dependence creates a “Achille’s heel” that may be exploited to develop new approaches to treat these viral infections. The general objective of my PhD is to understand the mechanisms by which DENV and ZIKV exploit the cellular functions for their advantage and to identify the host factors required for the initiation of their viral life cycle.ZIKV displays a cellular tropism for the brain and is responsible for severe neurological disorders such as congenital microcephaly in the fetus. The first part of my work was to characterize the role of the Axl receptor in the ZIKV neurotropism. Axl is a phosphatidylserine receptor belonging to the TAM receptor family, which is involved in the recognition and the removal of the apoptotic cells by phagocytosis. This work showed that Axl is highly expressed by microglial cells, radial cells and astrocytes in developing brain of fetuses and is important for ZIKV infection of these cells. We described two distinct roles played by Axl during ZIKV infection. First Axl, through its ligand Gas6, promotes the adsorption and the endocytosis of viral particles into glial cells. Second and simultaneously to the viral entry, the Gas6-ZIKV complexes act a ‘super agonist” that phosphorylate Axl tyrosine kinase domain to trigger signaling cascades that lead to the inhibition of the innate immune response and optimal viral replication. Furthermore, we identified two antagonists of Axl, the MYD1 and the R428, and showed their promising antiviral properties in vitro.The second part of my work aims to identify the cellular genes required for DENV infection. Using a genome-wide CRISPR-Cas9 screen, we identified the DPM1 and DPM3 proteins as new DENV host dependency factors. DPM1 and DPM3 are two subunits of the dolichol-phosphate-mannose synthase (DPMS) complex. This latter catalyzes the dolichol-phosphate-mannose synthesis, which provides the mannose required for the different glycosylation pathways in the ER lumen. Using DPM knockout cells, we showed that the DPMS complex facilitates the infection of the four DENV serotypes as well as other flaviviruses such as ZIKV and yellow fever virus (YFV). Using DPM1 mutants, we found that the catalytic activity of DPMS is crucial for DENV infection. We showed that DPMS complex plays several functions during the DENV life cycle. This complex is necessary for the replication of the viral genome, and is also required for the N-glycosylation of structural viral proteins, which allows their correct folding.In conclusion, this PhD work provides new insights for our understanding of the entry and replication mechanisms of two major arboviruses. These studies identified Axl and the DPMS complex as important cellular factors required for ZIKV and DENV life cycle and suggest that targeting these molecules may represent new strategies to combat DENV and ZIKV infection.
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Submitted on : Wednesday, January 6, 2021 - 4:23:08 PM
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Athena Labeau. Identification et caractérisation des facteurs cellulaires requis pour l’infection du virus Zika et du virus de la Dengue. Médecine humaine et pathologie. Université de Paris, 2019. Français. ⟨NNT : 2019UNIP7060⟩. ⟨tel-03100476⟩



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