Viral Mediated Type I Interferon Induction

描述(本研究计划的长期目标是确定不同的信号转导途径在应对DNA和RNA病毒感染时诱导干扰素(IFN)的机制。为了对抗病毒感染，大多数有核脊椎动物细胞都能够产生被称为I型IFN的细胞因子，这些细胞因子通过I型干扰素受体(IFNAR1)发出信号，导致JAK/STAT途径的激活，随后诱导大量在抗病毒反应中重要的基因。另一方面，作为共同进化的结果，许多病毒已经开发出抑制宿主细胞产生或反应干扰素的能力的策略。为了了解这种宿主/病原体相互作用的网络如何导致疾病，我们需要定义特定的干扰素诱导途径。与其他研究小组一起，我们已经证实Toll样受体(TLRs)可以通过激活干扰素调节因子IRF3和IRF7来介导干扰素的产生和抗病毒反应。最近的研究也发现RIG-I样受体(RIG-I like Receptor，RLR)家族成员是细胞内的核酸传感器，可以检测病毒的RNA序列；然而，负责识别细胞内病毒DNA的受体仍有待确定。我们实验室的研究一直集中在鉴定中间信号成分和通路，这些中间信号成分和通路将不同的模式识别受体，如TLRs和RLRs，连接到宿主抵抗病毒感染的先天性免疫反应中常见的依赖IRF3/7的干扰素诱导。令人惊讶的是，我们发现，尽管肿瘤坏死因子受体相关因子3(TRAF3)缺陷细胞在对RNA病毒感染的干扰素诱导方面存在缺陷，但它们在应对DNA病毒感染时会产生高水平的干扰素。这项应用的目的是从功能和机制上了解TRAF3等关键信号分子在宿主抵御DNA和RNA病毒感染时的生物防御作用。我们建议进行实验，以了解TRAF3如何在调节RNA和DNA诱导的I型干扰素诱导方面具有相反的功能。我们将确定通过激活非规范的NF-kB激活途径来增强干扰素的产生以对抗DNA病毒感染的机制和潜在的应用。我们还将确定一个新的含有DNA传感器的类似Rig-I的死盒的作用和特异性，并剖析其在宿主对DNA病毒的应答中介导的I型干扰素诱导途径。

DESCRIPTION (provided by The long term goal of this research proposal is to determine the mechanisms by which different signal transduction pathways lead to Interferon (IFN) induction in response to infections with DNA and RNA viruses. To combat viral infections most nucleated vertebrate cells are able to produce cytokines known as type I IFNs, which signal through the type I IFN receptor (IFNAR1), leading to activation of the JAK/STAT pathway and subsequent induction of a large set of genes important in antiviral responses. On the other hand, as a result of co-evolution, many viruses have developed strategies to inhibit the ability of host cells to either produce or respond to IFN. To understand how this network of host/pathogen interactions leads to disease, we need to define specific IFN induction pathways. Together with other groups, we have previously demonstrated that Toll-Like Receptors (TLRs) can mediate IFN production and antiviral responses through activation of IFN regulatory factors IRF3 and IRF7. Recent studies have also uncovered RIG-I like receptor (RLR) family members as intracellular nucleic acid sensors that can detect viral RNA sequences; however, the receptors responsible for recognizing intracellular viral DNA still remain to be determined. Research in our laboratory has been focused on identifying the intermediate signaling components and pathways that link different pattern recognition receptors, like TLRs and RLRs, to the common IRF3/7-dependent IFN induction in host innate immune responses against viral infections. Surprisingly, we have found that while TNF receptor associated factor 3 (TRAF3) deficient cells are defective in IFN induction in response to RNA viral infections, they produce elevated levels of IFN in response to DNA viral infections. The goal of this application is to gain a functional and mechanistic understanding of critical signaling molecules such as TRAF3 in host biodefense against DNA and RNA viral infections. We propose experiments to understand how TRAF3 has opposite functions in regulating RNA versus DNA induced type I interferon inductions. We will determine the mechanism responsible for and potential application of enhancing interferon production against DNA viral infection by activation of the non-canonical NF-kB activation pathway. We will also define the role and specificity of a new RIG-I like DEAD box containing DNA sensor and dissect its mediated type I interferon induction pathway in host response to DNA viruses.