PhD defense of Jason Decotter on december 6th 2023

Jason DECOTTER defended his PhD thesis on Wednesday, December 6, 2023, at 1 p.m. in the Charpak amphitheater at the University of Reunion Island.

Biology of emerging flaviviruses Zika and Dengue: Importance of the structural protein M

Abstract: Zika virus (ZIKV) and Dengue virus (DENV) are major arboviruses in terms of public health. Belonging to the genus Flavivirus (family Flaviviridae), ZIKV and DENV are primarily transmitted by mosquitoes of the Aedes genus. Over the past 30 years, the emergence of flaviviruses has only increased with a geographical expansion, particularly in tropical and subtropical regions of the planet. ZIKV is distinguished into two main lineages, Asian and African, which exhibit distinct pathogenesis and molecular responses. The Asian lineage contains almost all strains that have caused epidemic outbreaks. DENV is classified into several genotypes and four antigenically distinct serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. Recent dengue epidemics in tropical regions have been mainly associated with serotype DENV-2 and the increasing geographical distribution of the Cosmopolitan genotype. Over the last decade, territories in the southwest Indian Ocean (SWIO) have experienced rapid dengue outbreaks, with several tens of thousands of infection cases reported on Réunion Island between 2018 and 2023. The presence of vector mosquitoes and favorable environmental conditions may contribute to the endemicity of DENV and potential introduction of ZIKV on Réunion Island. In response to this observation, the UMR PIMIT has launched several research programs focusing on studying viral proteins known for their role in the pathogenicity of DENV and ZIKV flaviviruses. In the context of my thesis, my work focused on studying the membrane (prM/M) and envelope (E) structural proteins of these viruses, which are known to be essential for viral particle structure and infectivity, as well as host-pathogen interactions and immune response activation. Molecular analysis of Asian and African strains of ZIKV allowed us to identify the substitution of three residues at positions E-152, E-156, and E-158 in the glycosylation loop (GL) of the E protein. My work demonstrated the major role of residues E-152/156/158 in the antigenic reactivity of ZIKV GL, with their substitution resulting in loss of glycosylation motif and conformational changes disrupting E protein recognition by neutralizing antibodies. The prM/M protein of flaviviruses, which acts as a chaperone for proper folding of the E protein, appears to harbor viral determinants associated with flavivirus pathogenicity. The ectodomain of the M protein contains a pro-apoptotic peptide named ZAMP in ZIKV and D2AMP in DENV-2. We demonstrated for the first time, to our knowledge, that pro-apoptotic activity was associated with the ZAMP and D2AMP peptides, while showing the significant role of residues M-33/35/38 in this pro-apoptotic activity. Furthermore, a large part of my work focused on characterizing prM and E proteins of DENV-2 viral strains of the Cosmopolitan genotype found in the SWIO region. We demonstrated that the nature of the residue at position M-36 of the M protein impacts the biological behavior of prM/M and E proteins. Our results reveal that the substitution of an Ile residue with Val at position M-36 affects the expression and cytotoxicity of the E glycoprotein expressed as a prME complex and the ability of the D2AMP oligopeptide to activate the apoptotic pathway. My thesis work as a whole provides new insights into the biological characteristics of prM and E structural proteins, which will contribute to a better understanding of the pathogenicity of ZIKV and DENV-2 Cosmopolitan genotype flaviviruses found in the SWIO region.

Members of the jury
Pr. Didier Hober (CHU, Université de Lille)
Pr. Nathalie Chazal (IRIM, Université de Montpellier)
Pr. Marie-Paul Gonthier (DéTROI, Université de La Réunion)
Dr. Marie-Pierre Courageot (BioSpecT, Université de Reims)
Dr. Vincent Lotteau (CIRI, Lyon)
Dr. Gilles Gadea (IRCM, Montpellier)
Pr. Philippe Desprès (UMR PIMIT, Université de La Réunion)

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