Role of IRF3 and RXRa Crosstalk in Host Response to Viral Infections

这一应用的长期目标是更好地阐明其机制和生物学意义。 先天免疫反应和核激素受体在宿主防御中的串扰 感染和与病原体相关的代谢性疾病。我们实验室的初步数据发现了一种新的 干扰素调节因子3(IRF3)依赖而非I型干扰素非依赖途径 对病毒产物刺激或病毒感染的先天免疫反应，可导致强转录 抑制维甲酸X受体a(RXRA)。由于RXRA是大多数情况下的主要杂二聚体伙伴 核激素受体参与了许多细胞代谢过程，我们假设抑制 RXRA及其调控基因在病毒感染过程中的表达可能参与病毒相关性肝炎的发病 代谢性疾病，如热业S综合征，这是一种肝毒性疾病，当儿童服用 在病毒感染的情况下服用阿司匹林。此外，我们实验室的其他初步数据显示， 核激素受体激动剂可以抑制抗病毒基因的诱导，促进病毒复制。 因此，我们还假设，通过先天免疫反应抑制核激素受体 可能有助于适当的抗病毒反应。在本应用程序中，我们将确定角色和机制 抗病毒免疫反应和核激素受体之间的串扰 肝脏毒性和宿主对病毒感染的防御。我们计划首先开发模拟的老鼠模型 雷氏S综合征与对乙酰氨基酚所致肝毒性。然后我们将使用这些小鼠模型 为了确定由串扰引起的肝毒性的分子机制 抗病毒免疫反应和核激素受体。最后，我们将分析核的影响 激素受体及其激动剂对抗病毒先天免疫反应的抑制作用 天然免疫反应所产生的核激素受体是宿主防御病毒所必需的 感染。我们相信我们对先天免疫反应和核之间的串扰的研究 激素受体介导的新陈代谢不仅有助于我们理解 病毒诱导的代谢性疾病和药物诱导的免疫抑制，但也将提供新的策略 预防或治疗病毒感染患者及其相关代谢性疾病。

The long term goal of this application is to greater elucidate the mechanisms and biological significance of crosstalk between the innate immune response and nuclear hormone receptors in host defense against infections and in pathogen-associated metabolic diseases. Preliminary data in our lab has identified a novel Interferon Regulatory Factor 3(IRF3)-dependent but type I interferon independent pathway induced during innate immune response to viral product stimulation or viral infection, which can lead to strong transcriptional repression of Retinoid X Receptor a (RXRa). As RXRa is the major heterodimer partner for most of the nuclear hormone receptors involved in numerous cellular metabolic processes, we hypothesize that repression of RXRa and its regulated genes during viral infections can contribute to the pathogenesis of viral associated metabolic diseases such as Reye¿s Syndrome, a hepatotoxicity disease that occurs when children are given aspirin in the context of a viral infection. Furthermore, additional preliminary data in our lab showed that nuclear hormone receptor agonists can suppress the induction of antiviral genes and promote viral replications. We therefore also hypothesize that repression of nuclear hormone receptors by the innate immune response may contribute to a proper anti-viral response. In this application, we will determine the roles and mechanisms of the crosstalk between anti-viral immune response and nuclear hormone receptors in both viral associated hepatotoxicity and host defense against viral infections. We plan to first develop mouse models that mimic Reye¿s Syndrome and acetaminophen (APAP)-induced hepatotoxicity. We will then use these mouse models to determine the molecular mechanisms responsible for hepatotoxicity resulting from the crosstalk between anti-viral immune response and nuclear hormone receptors. Finally, we will analyze the effects of nuclear hormone receptors and their agonists on anti-viral innate immune responses to determine if the repression of nuclear hormone receptors by innate immune response is necessary for the proper host defense against viral infections. We believe our investigation of the crosstalk between the innate immune response and nuclear hormone receptor-mediated metabolism will not only help us to understand the mechanisms responsible for viral induced metabolic diseases and drug induced immuno-suppressions but will also provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases.