A novel regulator of extracellular nucleic acid sensing

摘要 病原体来源的RNA代表了一种典型的病原体相关分子模式(PAMP)，其 模式识别受体(PRR)检测是先天免疫的一个基本特征。胞外 RNA主要通过内体Toll样受体(TLRs)检测，包括那些检测单个Toll样受体的受体。 链RNA(TLR7/TLR8)和双链RNA(TLR3)。通过内体TLRs诱导的信号传导 产生包括I型干扰素在内的细胞因子，可引起抗病毒状态并广泛激活 免疫系统。DNA和RNA的传感都受到核酸加工的严格控制 酶，这可能是产生DNA/RNA配体以供PRR识别所需的，以及 防止核酸的异常积累。然而，人们对可能控制细菌生长的酶知之甚少。 胞外RNA及其内体TLRs的传感。我们已经确定了一种候选酶，它可能 代表TLR介导的细胞外RNA传感的负调节因子；因此，该蛋白可能 抑制抗菌素免疫反应过程中的炎症和组织损伤，以及限制 自身免疫性疾病中的自身反应性。在目标1中，我们将使用增益法和损失法进行测试 它如何影响内体TLRs对RNA和相关PAMP的感知。在目标2中，我们将测试它在 自身免疫的动物模型，以及抗病毒免疫反应。拟议的研究可能会有所帮助。 鉴定一种新的先天免疫感知调节因子并为其作为蛋白质的开发提供理论基础 治疗炎症性和/或自身免疫性疾病。

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.