Viral Mediated Type I Interferon Induction

摘要 这项研究计划的长期目标是确定重要的 肿瘤坏死因子受体相关因子3和核因子-κB诱导激酶在调节宿主中的作用 防御病毒感染和自身免疫反应。我们在20多年前确定TRAF3是一种 与包括CD40、BAFFR和LTβR在内的肿瘤坏死因子受体亚群相关的接头分子 随后产生了TRAF3基因敲除小鼠，并发现它们在出生后两周内死亡，过度- 反应性炎症反应。在过去的几年里，我们定义了TRAF/CIAP/Nik复合体 负责通过结构性降解抑制未刺激细胞中非规范的NF-κB活性 尼克。我们的发现的意义得到了以下观察的支持：编码基因的突变 TRAF/CIAP/Nik复合体的组成部分与炎症性和自身免疫性疾病有关，如 以及几种血液癌，如多发性骨髓瘤和弥漫性B细胞淋巴瘤。我们最近 研究还发现了一种新的Nik/ikk/CRL蛋白复合体，它起到负反馈控制的作用 在防止受体激活后过度反应的非典型性NF-κB活性方面。另外，我们初步的 研究发现了一种新的NiK/STING/TBK1复合体，它可以增强DNA诱导的I型干扰素 (干扰素-I)生产。基于我们的遗传和生化研究，我们发现TRAF3在 调节DNA与RNA诱导的干扰素-I的诱导。我们已经提供了证据，证明非 典型的核因子-κB和干扰素-I诱导途径可能不仅在调节宿主防御中发挥重要作用 在抗DNA病毒感染的同时，也在DNA和BAFF介导的干扰素-I和自身抗体的合成中发挥作用。 抗体，这是某些自身免疫性疾病的标志，如狼疮。我们的总体假设是 TRAF3和NIK在调节抗病毒免疫和自身免疫反应中发挥重要作用 控制非典型的核因子-κB的激活及其与干扰素-I的产生的串扰。我们的目标是获得一个 TRAF3和NIK在调节非典型性NF-κB激活中的功能和机制 干扰素-I的生产。在目标1中，我们将定义Nik/IKK/CRL复合体的主要组件并确定 它们在非典范的NF-κB途径负反馈调控中的作用。在目标2中，我们将定义 Nik/Sting/TBK1复合体的主要成分并确定它们在调节串扰中的作用 非典型的κ-B和干扰素-I诱导途径之间的关系。在目标3中，我们将确定 非典型性核因子-κB激活与干扰素-I应答在宿主防御中的串扰 感染及其与自身免疫性疾病的关系。最后，我们将探讨使用Small 作为保护病毒感染和治疗病毒感染的新药物的非典型性NF-κB途径的分子调节因子 自身免疫性疾病。我们相信，我们提议的研究将有助于未来在药理学上 干预传染病和自身免疫性疾病。

ABSTRACT The long term goal of this research proposal is to determine the mechanisms responsible for the important functions of TNF receptor associated factor 3 (TRAF3) and NF-κB inducing kinase (NIK) in regulating host defense against viral infections and autoimmune responses. We identified TRAF3 over 20 years ago as an adaptor molecule associated with a subset of TNF receptors including CD40, BAFFR and LTβR. We subsequently generated TRAF3 knockout mice and found that they die within two weeks after birth with over- reactive inflammatory responses. In the past several years, we have defined a TRAF/cIAP/NIK complex responsible for suppressing non-canonical NF-κB activity in unstimulated cells through constitutively degrading NIK. The significance of our findings is supported by the observation that mutations in the genes encoding components of the TRAF/cIAP/NIK complex are associated with inflammatory and autoimmune diseases, as well as several hematological cancers such as multiple myeloma and diffuse B-cell lymphoma. Our recent studies have also discovered a novel NIK/IKK/CRL protein complex, which acts as a negative feedback control in preventing over-reactive non-canonical NF-κB activity after receptor activation. In addition, our preliminary studies have identified a novel NIK/STING/TBK1 complex, which can enhance DNA-induced Type I interferon (IFN-I) production. Based on our genetic and biochemical studies, we found TRAF3 has opposing roles in regulating DNA vs. RNA-induced IFN-I induction. We have provided evidence that crosstalk between the non- canonical NF-κB and IFN-I indcution pathways may play important roles not only in regulating host defense against DNA virus infection but also in DNA and BAFF-mediated syngergistic pruduction of IFN-I and auto- antibodies, which are a hallmark of certain autoimmune diseases such as Lupus. Our overall hypothesis is that TRAF3 and NIK play important roles in regulating anti-viral immunity and auto-immune responses through controlling non-canonical NF-κB activation and its crosstalk with IFN-I production. Our goal is to gain a functional and mechanistic understanding on TRAF3 and NIK in regulating non-canonical NF-κB activation and IFN-I production. In Aim 1, we will define the major components of the NIK/IKK/CRL complex and determine their roles in the negative feedback control of the non-canonical NF-κB pathway. In Aim 2, we will define the major components of the NIK/STING/TBK1 complex and determine their roles in regulating the crosstalk between non-canonical NF-κB and IFN-I induction pathways. In Aim 3, we will determine the contributions of the crosstalk between non-canonical NF-κB activation and IFN-I responses in host defense against DNA virus infections and its association with autoimmune diseases. Finally, we will explore the possibility of using small molecular regulators of the non-canonical NF-κB pathway as novel agents to protect viral infections and treat autoimmune diseases. We believe our proposed studies will assist in future attempts to pharmacologically intervene against infectious and autoimmune diseases.