Cellular mechanisms of viral gene sensing and silencing

Viruses deliver their genomes to host cells either as DNA or RNA. The cell's principal defenses are to mount a potent immune response to viral RNA, and to prevent gene expression from viral DNA. These responses must be finely balanced as their inappropriate activation has been linked to severe autoimmune diseases including Aicardi-Goutières and Singleton-Merten syndromes. To be able to control these responses, we must first define the underlying mechanisms required for activation. We will use a complementary set of approaches to gain a view of how cells interact with viral genomes with unprecedented structural detail. High-resolution structural information has a powerful ability to generate insights into how molecules work and guide the design of potential therapeutics. Our work will establish fundamental principles of how cells calibrate their antiviral responses to prevent virus proliferation without triggering autoimmune responses. We expect to identify new pathogen vulnerabilities and suggest new therapeutic strategies.