Cellular mechanisms of viral gene sensing and silencing (360G-Wellcome-217191_Z_19_Z)

Viruses depend on cellular machinery to express and replicate their genes. Viral RNA must therefore be delivered or generated in the cytosol. Some viruses also deliver genomic DNA into the nucleus, for integration into the host cell genome. The cell’s principal innate defenses are to mount a potent inflammatory response upon sensing cytosolic viral RNA and to repress the transcription of integrated viral DNA. To be effective, these responses must be sensitive, specific and appropriately calibrated to minimize toxicity and autoinflammation. Our overarching goal is to gain a molecular understanding of how the cell recognizes cytosolic viral RNA and how it silences viral gene expression with the necessary sensitivity and specificity. In pursuit of this goal we are applying a complementary set of biophysical, biochemical and cell biological approaches, with a focus on using high-resolution structural information to obtain detailed mechanistic insights with atomic-level detail. Our key goals are to understand: -how cells distinguish viral from endogenous nucleic acids; -how the immune response against double-stranded RNA is generated and amplified; -how cells recognize and silence integrated viral DNA; This will provide invaluable insights on fundamental principles of host-pathogen recognition, chromatin regulation and host-virus coevolution.