Description du projet
Caractériser le complexe protéique déclenchant une réponse immunitaire antivirale
La protéine adaptatrice de signalisation antivirale mitochondriale ou MAVS (mitochondrial antiviral signalling) joue un rôle central dans la signalisation antivirale cellulaire en réponse aux infections par des virus à ARN, initiée par les récepteurs cytosoliques qui déclenchent la voie de l’interféron de type I via la MAVS. Des études récentes ont montré que l’ARN hélicase DDX3 est un nouveau membre du groupe de récepteurs cytosoliques viraux, nécessaire pour activer la MAVS au cours de la réponse antivirale. Le projet MDR, financé par l’UE, se concentrera sur la caractérisation structurelle et fonctionnelle du complexe MAVS-DDX3-ARN viral (MDR), en combinant des méthodes biophysiques et de biologie cellulaire. Le MDR joue un rôle central dans le déclenchement de la réponse immunitaire antivirale, ce qui en fait une cible pharmacologique potentielle.
Objectif
The mitochondrial antiviral signalling (MAVS) adaptor protein is a central signalling hub for host cells to mount an antiviral response following RNA virus infections, which is initiated by the cytosolic receptors that trigger the type-I interferon (INFs) path through the MAVS. Recently, it has been shown that the RNA helicase DDX3 is a novel atypical member of the viral cytosolic receptor pool and it is required to activate the MAVS during the antiviral response. In fact, DDX3 is crucial in the translation initiation of the HIV-1 RNA and it is identified as viral RNA sensor able to induce the antiviral immunity in dendritic cells (DCs). DDX3 binds to viral RNAs lacking the poly(A) tails, also known as abortive transcripts, and then associates with the MAVS to trigger the production of type I IFN.
Currently, it is unknown how the complex partners MAVS-DDX3-vRNA (MDR) interact for assembly and what is the MDR mechanism of action at molecular level.
The proposed research will be focused on the structural and functional characterization of the MDR complex by biophysical and cellular biology techniques. Notably, silencing DDX3 or MAVS expression suppress DC activation in response to HIV-1 infection, an event that in physiological condition is at the front line of host defence against the HIV-1. Therefore, the central role in triggering antiviral immune response makes MDR a strategic pharmacological target. However, addressing this task requires the MDR structure elucidation in order to exploit its molecular features to create a new generation of adjuvants in anti-retroviral therapy.
This research provides an understanding of how cellular protein sensors interact with retroviral RNA to trigger the native immune response and induce expression of antiviral proteins.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemultidrug resistance
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
1105AZ Amsterdam
Pays-Bas