A novel regulator of extracellular nucleic acid sensing

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ABSTRACT Pathogen-derived RNA represents a canonical pathogen-associated molecular pattern (PAMP), and its detection by pattern recognition receptors (PRR) is a fundamental feature of innate immunity. Extracellular RNA is detected primarily via endosomal Toll-like receptors (TLRs), including those detecting single- stranded RNA (TLR7/TLR8) and double-stranded RNA (TLR3). Signaling through endosomal TLRs induces the production of cytokines including type I interferons (IFN), which elicit antiviral states and broadly activate the immune system. Sensing of both DNA and RNA is tightly regulated by nucleic acid-processing enzymes, which may be required both to generate DNA/RNA ligands for recognition by PRRs, and to prevent aberrant accumulation of nucleic acids. However, little is known about the enzymes that may control extracellular RNA and its sensing by endosomal TLRs. We have identified a candidate enzyme that may represent a negative regulator of TLR-mediated extracellular RNA sensing; as such, this protein may dampen inflammation and tissue damage during antimicrobial immune responses, as well as restrict autoreactivity in autoimmune disease. In Aim 1, we will use gain and loss-of-function approaches to test how it affects the sensing of RNA and related PAMPs by endosomal TLRs. In Aim 2, we will test its role in animal models of autoimmunity, as well as in antiviral immune responses. The proposed studies may help identify a novel regulator of innate immune sensing and provide rationale for its development as a protein therapeutic in inflammatory and/or autoimmune diseases.