Nucleic acid detection in host defense and autoimmunity
Work in my laboratory is motivated by a simple question: how do cells detect virus infection? In recent years, a paradigm has emerged in which immune responses to viruses are initiated by sensors of viral nucleic acids. These sensors survey the interiors of nearly all of our cells for the presence of foreign RNA or foreign DNA. While this paradigm makes sense in light of the fact that the one invariant feature shared by all viruses is a genome composed of RNA or DNA, it also raises the fundamental question of how these receptors evolved to respond to foreign nucleic acids while ‘ignoring’ the billions of base pairs of DNA and the millions of molecules of RNA in every nucleated cell. Our goal is to understand the principles of self/non-self discrimination by nucleic acid sensors. To do this, we apply tools of genetics, cell biology, biochemistry, and molecular biology to study the innate immune pathways triggered by foreign DNA and RNA in mammalian cells. We define new components of these pathways, explore how viruses antagonize these responses, identify and characterize essential negative regulators of nucleic acid detection, and develop new mouse models and human cell lines to investigate the consequences of aberrant responses to self nucleic acids. Our work has been informed by the discovery of rare human diseases caused by excessive immune responses to self nucleic acids. In turn, our definition of the underlying mechanisms of these diseases has illuminated new opportunities for therapeutic intervention. Our ongoing, unpublished work has uncovered new nucleic acid detection pathways and unanticipated regulatory mechanisms that limit the antiviral response. We anticipate that our studies will have important implications for how to trigger optimal host responses to viruses and tumors and vaccines, and for how to turn these responses off in autoimmune settings.
Associate Professor, Immunology, University of Washington