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

描述（由申请方提供）：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IIFN型基因并建立细胞抗病毒状态。检测由生殖细胞编码的先天免疫受体介导，通常称为模式识别受体（PRR）。这些PRR，包括TLR（TLR 3、TLR 7、TLR 8和TLR 9）和细胞质RNA解旋酶（RIG-I、Mda-5和可能的其他），能够检测病毒核酸。双链RNA是病毒复制的关键特征，在内体区室中由TLR 5识别，或在细胞质中由RNA解旋酶识别。TLR 5和RIG-I下游的I型IFN基因诱导需要IRF 3的信号依赖性磷酸化，使IRF 3能够二聚化，易位到细胞核并激活IFN基因转录。TBK-1和IKK？磷酸化并激活IRF 3。TBK 1和IKK？是TLR和RNA解旋酶信号传导所必需的。然而，关于TLR或RNA解旋酶与这些激酶之间的分子联系，我们知之甚少。我们的目标是详细了解这些分子事件。我们将使用生物化学，视觉和分子遗传学方法的组合来了解病毒病原体在感染期间如何被先天免疫反应识别，以及这些PRR途径如何激活这些激酶。这些研究的成功完成将有助于我们了解负责病毒病原体先天免疫感应的分子机制。这些研究对于合理设计治疗剂以增强宿主防御感染性病原体的先天免疫也至关重要。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））的发病机制中也占据中心地位，因此更清楚地了解这些重要免疫介质的调节也将有助于治疗这些和其他相关的自身免疫性疾病。总之，非常详细地定义这些途径将是重要的，使我们能够设计可用于打开这些激酶的治疗方法，作为一种帮助清除病毒病原体的方式，这将对宿主有利，或者在诸如自身免疫性疾病的情况下关闭它们，其中IFN的产生对宿主不利。

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.