Stephen Cusack

Host Institution : EMBL

Laboratory : EMBL-Grenoble-UVHCI (CNRS/EMBL/UJF)

Call for Projects : Advanced (LS1)

Project name : V-RNA – Two facets of viral RNA: mechanistic studies of transcription and replication by influenza-like viral polymerases and detection by the innate immune system

Amount : 2.37 M€

Description :

RNA viruses infect cells to replicate and repackage their genomes in progeny virions. In response, the cellular innate immune system detects viral RNA and triggers powerful anti-viral countermeasures. This proposal aims to elucidate atomic resolution molecular mechanisms associated with these conflicting interests, and will address the following questions:

firstly, how do RNA polymerases of segmented, negative sense, single-stranded RNA viruses such as influenza and bunyaviruses transcribe and replicate viral RNA and secondly, how do RIG-I like helicases, intracellular, innate immune, pattern recognition receptors, selectively detect RNA only of viral origin, thus triggering interferon production and induction of the anti-viral state?
A third, more exploratory part of the proposal will use proteomics analysis to identify all host factors that are bound to viral mRNAs in influenza virus infected cells.

The interdisciplinary project will combine state-of-the-art structural biology with cell-based functional assays and global analysis. Results will advance fundamental understanding of polymerases and helicases, both complex RNA-dependent molecular machines, give new insight into the regulation of innate immune receptor activation and signalling, and shed new light on RNA metabolism in the perturbed environment of the infected cell.

They will also impact virology and public health by bringing new knowledge on RNA virus-host interactions, virus evolution and inter-species transmission. More pragmatically the project will boost structure-based anti-viral drug development targeting serious and/or emerging human pathogens such as influenza A, which poses the perennial threat of a devastating pandemic, and the many disease causing bunyaviruses, which in a globally warming world could spread unpredictably. The V-RNA project thus forms a coherent whole covering important protagonists in the virus-versus-host-versus-virus molecular warfare centred around viral RNA.