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

本申请的长期目标是更好地阐明 天然免疫反应和核激素受体在宿主防御中的相互作用 感染和病原体相关的代谢疾病。我们实验室的初步数据显示 干扰素调节因子3（IRF3）依赖性但I型干扰素非依赖性途径诱导 对病毒产物刺激或病毒感染的先天免疫应答，其可导致强转录 视黄酸X受体a（RXRa）的抑制。由于RXRa是大多数人的主要异二聚体伴侣， 核激素受体参与许多细胞代谢过程，我们假设， RXR α及其调控基因在病毒感染过程中的表达可能有助于病毒相关性疾病的发病机制， 代谢性疾病，如雷氏综合征，一种肝毒性疾病，当儿童被给予 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抑制抗病毒基因的诱导并促进病毒复制。 因此，我们还假设，先天免疫反应对核激素受体的抑制 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，在两个病毒相关的 肝毒性和宿主对病毒感染防御。我们计划首先开发小鼠模型， Reye综合征和对乙酰氨基酚（APAP）诱导的肝毒性。然后我们将使用这些小鼠模型 确定肝毒性的分子机制， 抗病毒免疫反应和核激素受体。最后，我们将分析核武器的影响。 激素受体及其激动剂对抗病毒先天免疫应答的影响，以确定是否抑制了 核激素受体通过先天免疫应答是宿主防御病毒感染所必需的 感染.我们相信我们对先天免疫反应和核免疫反应之间的串扰的研究， 激素受体介导的代谢不仅有助于我们了解 病毒诱导的代谢疾病和药物诱导的免疫抑制，但也将提供新的策略 以预防或治疗患有病毒感染及其相关代谢疾病的患者。

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.