Regulation of Type I Interferon Gene Expression in the Innate Immune Response

描述(申请人提供)：成功的宿主防御病毒感染，依赖于病毒的早期检测，随后快速产生I干扰素基因，并建立细胞抗病毒状态。检测是由生殖系编码的先天性免疫受体介导的，通常被称为模式识别受体(PRR)。这些PRRs既包括TLR3、TLR7、TLR8和TLR9，也包括细胞质RNA解旋酶(RIG-I、MDA-5等)，能够检测病毒核酸。双链RNA是病毒复制的关键标志，TLR5在内体隔间识别，如果在细胞质中，则由RNA解旋酶识别。TLR5和RIG-I下游I型干扰素基因的诱导需要IRF3的信号依赖性磷酸化，使IRF3二聚化、转位到细胞核并激活干扰素基因转录。TBK-1和IKK？使IRF3磷酸化并激活。Tbk1和ikk？是TLR和RNA解旋酶信号转导所必需的。然而，关于将TLR或RNA解旋酶与这些激酶联系起来的分子事件，人们知之甚少。我们的目标是详细了解这些分子事件。我们将结合使用生化、视觉和分子遗传学方法来了解病毒病原体是如何被感染期间的先天性免疫反应识别的，以及这些PRR途径是如何激活这些激酶的。这些研究的成功完成将有助于我们理解病毒病原体先天免疫感知的分子机制。这些研究对于合理设计治疗药物以增强宿主对感染性病原体的天然免疫防御也是至关重要的。由于I型干扰素在系统性和器官特异性自身免疫性疾病包括系统性红斑狼疮(SLE)的发病机制中也占有中心地位，因此对这些重要免疫介质的调控的更清楚的了解也将有助于这些疾病和其他相关自身免疫性疾病的治疗。总之，非常详细地定义这些途径将是重要的，使我们能够设计可以用来启动这些激酶的治疗方法，作为一种辅助清除病毒病原体的方式，这将对宿主有利，或者在自身免疫性疾病等情况下关闭它们，其中产生干扰素对宿主不利。

DESCRIPTION (provided by applicant): Successful host defense against viral infection, relies on the early detection of the virus followed by the rapid production of type IIFN genes and the establishment of a cellular anti-viral state. Detection is mediated by germline-encoded innate immune receptors, often referred to as pattern recognition receptors (PRRs). These PRRs, which include both TLRs (TLR3, TLR7, TLR8 and TLR9) and cytoplasmic RNA helicases (RIG-I, Mda-5 and possibly others) are capable of detecting viral nucleic acids. Double stranded RNA, a key signature of viral replication is recognised by TLR5, in the endosomal compartment, or by the RNA helicases, if in the cytoplasm. Type I IFN gene induction downstream of TLR5 and RIG-I requires the signal-dependent phosphorylation of IRF3, enabling IRF3 to dimerize, translocate to the nucleus and activate IFN gene transcription. TBK-1 and IKK? phosphorylate and activate IRF3. TBK1 and IKK? are required for TLR and RNA helicase signaling. Little else is known however, about the molecular events that connect TLRs or RNA helicases with these kinases. Our goal is to understand in detail these molecular events. We will use a combination of biochemical, visual and molecular genetic approaches to understand how viral pathogens are recognized by the innate immune response during infection and how these PRR- pathways activate these kinases. Successful completion of these studies will help us understand the molecular mechanisms responsible for the innate immune sensing of viral pathogens. These studies are also vital for the rational design of therapeutic agents to enhance innate immunity in host defense against infectious pathogens. Since type I IFNs also occupy centre stage in the pathogenesis of systemic and organ-specific autoimmune diseases including Systemic Lupus Erythematosus (SLE), a clearer understanding of the regulation of these important immune mediators will also be useful for the treatment of these and other related autoimmune diseases. In summary, defining these pathways in great detail will be important to allow us to design therapies which could be used to turn on these kinases, as a way to assist in clearance of a viral pathogen, which would be advantageous to the host, or alternatively, to turn them off in situations, such as autoimmune disease, where production of IFN is disadvantageous to the host.