Viruses depend on host cell 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, where it can be integrated into the host cell genome. The cell’s principal innate antiviral defence is an inflammatory response that is activated upon sensing cytosolic viral RNA. An additional defence mechanism is the transcriptional silencing of integrated viral DNA. Our overarching goal is to gain a mechanistic understanding at the molecular level of how the cell detects cytosolic viral RNA and how it silences viral gene expression. 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. This will help establish basic principles of how viruses and cells coexist in health and disease.
Key Research Questions
How do cells distinguish pathogenic viral nucleic acids from non-pathogenic endogenous nucleic acids?
How is the inflammatory innate immune response against viral double-stranded RNA in the cytosol generated and amplified?
How do cells recognize and silence the expression of integrated viral DNA?
What are the cellular functions of endogenized viral sequences?
Why these questions are important?
Viral infection is detected primarily by innate immune sensors that recognize RNA or DNA with virus-specific chemical signatures. Pathogenic viral and non-pathogenic endogenous nucleic acids are often difficult to distinguish. Endogenous RNA is abundant in the cytosol, and viruses have evolved various strategies to mask their most proinflammatory nucleic acid signatures. Efficient proofreading mechanisms are necessary for cells to effectively detect infection while avoiding autoinflammation from endogenous nucleic acids.
Innate immune signalling pathways have been mapped out in some detail and we have a basic understanding of how cytosolic viral RNA is recognized by the cell. However, the proofreading mechanisms that allow innate immune sensors to selectively activate signalling in response to viral RNA while minimizing autoimmune signalling are poorly understood.
Cells face the additional challenge of identifying and transcriptionally silencing integrated viral DNA sequences. These include viral DNA inherited from previous generations, which accounts for half of the human genome. Epigenetic transcriptional silencing of integrated viral genes and endogenized viral sequences is emerging as a central mechanism to maintain genome integrity and prevent harmful gene expression or transposition. However, silencing can also impede treatment and eradication of certain viruses, including most notably HIV. The pathways and molecular mechanisms governing viral gene silencing in human cells remain largely uncharted.
Understanding how cells distinguish viral RNA from cellular RNA, how they mount innate immune responses against viral RNA, and how they repress their transcription of integrated DNA will provide invaluable insights on general principles of host-pathogen recognition, chromatin regulation and host-virus coevolution. We expect this work to suggest new strategies for immunomodulatory therapy and virus eradication.
We employ a diverse set of complementary biophysical approaches including cryo-electron microscopy (cryoEM), X-ray crystallography, solution biophysics, fluorescence microscopy and cell biological approaches to understand the cellular mechanisms of viral gene sensing and silencing in molecular-level detail.
Hwang MS, Boulanger J … Modis Y;MAVS oligomers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling. FEBS Journal 2018. DOI: 10.1111/febs.14772
Yu Q, Qu K & Modis Y; CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis. Molecular Cell 2018. DOI: 10.1016/j.molcel.2018.10.012
Douse CH, Bloor S … Modis Y; mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms. Nature Communications 2018. DOI: 10.1038/s41467-018-03045-x
Fenwick MK … Modis Y … Ealick SE; Structural studies of viperin, an antiviral radical SAM enzyme. Proceedings of the National Academy of Science 2017. DOI: 10.1073/pnas.1705402114