Description du projet
Déchiffrer les mécanismes du processus d’infection virale
Les mécanismes moléculaires de l’infection virale et de l’évasion du système immunitaire chez les hôtes mammifères restent mal compris. Le projet CHUbVi, financé par l’UE, identifiera les voies impliquées dans le processus d’infection, en vue de fournir des cibles moléculaires pour des composés antiviraux à large spectre. Grâce à des études précédentes, l’équipe a constaté que des chaînes libres d’ubiquitine et d’histone désacétylase-6 agissent comme médiateurs essentiels de l’entrée virale par le biais de la voie de transformation de l’agrésome, qui organise les protéines mal repliées dans des endroits déterminés lorsque le système de dégradation des protéines de la cellule est submergé. Des études détaillées sur l’implication de cette voie permettront le développement d’essais cellulaires et biochimiques sur l’infection de grippe A, ainsi que des recherches pour savoir si cette voie est liée au processus d’infection d’autres virus, dont le Zika, la dengue, l’Ebola et le MERS.
Objectif
Viruses such as Influenza A (IAV) and others remain one of the greatest threats to human health and society. Despite their danger and widespread prevalence, the molecular mechanisms of how they infect mammalian hosts and evade the immune system remains poorly understood. Recent studies from our team implicate two common proteins – HDAC6 and unanchored ubiquitin chains – in host cells as key mediators of viral entry via the aggresome processing pathway. This discovery offers a new line of investigation for understanding and preventing viral infections.
By identifying the pathways and interactions involved in this infection process, we will provide new molecular targets for the development of broad-spectrum antiviral compounds. Multidisciplinary studies by a team consisting of a molecular biologist, a virologist, and a chemical biologist will use a diverse set of tools to validate these pathways and gain fundamental knowledge about their regulation. To achieve this, detailed studies on the exact nature of the ubiquitin chains needed to activate HDAC6 will allow the development of biochemical and cellular assays of Influenza A infection and enable the determination of the precise mechanism and the downstream cellular pathways necessary for viral infection. The chemical synthesis of labeled ubiquitin chains will support detailed structural studies and a clear understanding of how they are formed and packaged into infectious viral particles. The strong possibility that numerous other virus types also utilize this pathway will be tested with life-threatening agents of current concern including Zika, Dengue, Ebola, and MERS viruses.
By demonstrating – with both biological approaches and small molecule compounds – that blocking these cellular processes in cells and animal models reduces viral infection, this project will provide a wealth a novel insights and the basis for the development of a new generation of anti-viral therapies.
Champ scientifique
- natural sciencesbiological sciencesmicrobiologyvirology
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesebola
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-SyG - Synergy grantInstitution d’accueil
4058 Basel
Suisse