Descrizione del progetto
Caratterizzazione del complesso proteico che innesca una risposta immunitaria antivirale
La proteina adattatrice di segnalazione antivirale mitocondriale (MAVS, Mitochondrial Antiviral Signalling) svolge un ruolo chiave nella segnalazione antivirale delle cellule in risposta alle infezioni virali a RNA, attivata dai recettori citosolici che innescano la via dell’interferone di tipo I attraverso i MAVS. Studi recenti hanno dimostrato che l’RNA elicasi DDX3 è un nuovo componente del gruppo di recettori virali citosolici, necessario per attivare i MAVS durante la risposta antivirale. Il progetto MDR, finanziato dall’UE, si concentrerà sulla caratterizzazione strutturale e funzionale del complesso MAVS-DDX3-RNA virale (MDR), impiegando metodi della biofisica e della biologia cellulare. L’MDR svolge il ruolo chiave di attivazione della risposta immunitaria antivirale il che lo rende un potenziale bersaglio farmacologico.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
1105AZ Amsterdam
Paesi Bassi