Project description DEENESFRITPL Characterisation of the protein complex that triggers an antiviral immune response The mitochondrial antiviral signalling (MAVS) adaptor protein plays a central role in cell antiviral signalling in response to RNA virus infections, initiated by the cytosolic receptors that trigger the type-I interferon pathway via the MAVS. Recent studies showed that the RNA helicase DDX3 is a new member of the viral cytosolic receptor pool, required to activate the MAVS during the antiviral response. The EU-funded MDR project will focus on the structural and functional characterisation of the MAVS-DDX3-viral RNA (MDR) complex, using biophysical and cellular biology methods. MDR has the central role in triggering an antiviral immune response, making it a potential pharmacological target. Show the project objective Hide the project objective Objective 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. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemultidrug resistancemedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals Keywords Molecular Immunology Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2018 - Individual Fellowships Call for proposal H2020-MSCA-IF-2018 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM Net EU contribution € 187 572,48 Address MEIBERGDREEF 15 1105AZ Amsterdam Netherlands See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 187 572,48
