Descripción del proyecto
Caracterización del complejo proteico que desencadena una respuesta inmunitaria antivírica
El adaptador proteico de señalización antivírica mitocondrial (MAVS, por sus siglas en inglés) desempeña un papel esencial en la señalización antivírica celular en respuesta a infecciones por virus de ARN, iniciada por los receptores citosólicos que activan la vía del interferón de tipo I a través del MAVS. Estudios recientes identificaron la ARN helicasa DDX3 como un nuevo miembro del grupo de receptores citosólicos víricos y que es necesario para activar el MAVS durante la respuesta antivírica. En el proyecto MDR, financiado con fondos europeos, se llevará a cabo la caracterización funcional y estructural del complejo MAVS-DDX3-ARN vírico (MDR, por sus siglas en inglés) mediante técnicas biofísicas y de biología celular. El complejo MDR desempeña un papel fundamental a la hora de desencadenar una respuesta inmunitaria antivírica, lo que lo convierte en una posible diana farmacológica.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
1105AZ Amsterdam
Países Bajos