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

描述（由申请人提供）：本申请的长期目标是阐明宿主防御感染和病原体相关代谢疾病中先天免疫应答与核激素受体之间串扰的机制和生物学意义。我们实验室的初步数据已经确定了一种新的干扰素调节因子3（IRF3）依赖性，但I型干扰素非依赖性途径诱导先天免疫反应的病毒产物刺激或病毒感染，导致强烈的转录抑制类维生素A X受体1（RXR 1）。由于RXR 1是参与许多细胞代谢过程的大多数核激素受体的主要异源二聚体伴侣，我们假设在病毒感染期间RXR 1及其调控基因的抑制可以对宿主代谢特别是药物代谢产生强烈影响。我们进一步表明，这可能有助于病毒相关代谢疾病的发病机制，如Reye综合征，一种肝毒性疾病，当儿童在病毒感染的背景下服用阿司匹林时发生，或对乙酰氨基酚（APAP）诱导的肝毒性，约占美国急性肝功能衰竭的一半。有趣的是，我们的初步研究表明，对病毒产物的先天免疫反应可以增强阿司匹林诱导的肝毒性，但保护APAP诱导的肝毒性，这可以解释为什么在病毒感染期间，患者使用泰诺比阿司匹林更安全。这些结果进一步表明，根据药物的性质，病毒感染可能会不同程度地影响药物中间代谢产物的积累，这可能导致对宿主组织的相反毒性作用。在本申请中，我们将首先开发模拟Reye综合征和对乙酰氨基酚（APAP）诱导的肝毒性的小鼠模型。然后，我们将使用这两个相反的药物代谢模型作为例子，以确定如何先天免疫反应病毒感染可以差异改变不同药物的稳定性或毒性。此外，我们实验室的其他初步数据表明，核激素受体激动剂可以抑制抗病毒基因的诱导并促进病毒复制。因此，我们还假设，抑制核激素受体的先天免疫反应可能有助于有效的抗病毒反应。我们将进一步分析核激素受体及其激动剂对抗病毒先天免疫应答的作用，以确定先天免疫应答对核激素受体的抑制是否是宿主对抗病毒感染的适当防御所必需的。我们相信我们对先天免疫应答和核激素受体介导的代谢之间的串扰的研究不仅有助于我们理解病毒诱导的代谢疾病和药物诱导的免疫抑制的机制，而且还将提供预防或治疗病毒感染及其相关代谢疾病的新策略。公共卫生相关性：包括代谢性疾病在内的许多疾病都与病毒感染有关。另一方面，许多代谢产物和药物也会影响我们身体抵御入侵病毒的能力。然而，负责这种协会的分子机制尚不清楚。我们最近发现了宿主免疫反应和代谢之间的一种新的串扰，这不仅可以解释病毒相关的肝脏疾病，如Reye综合征，还可以解释代谢药物如何抑制宿主对病毒感染的反应。对这种串扰的进一步研究将为预防或治疗病毒感染及其相关代谢性疾病（如对乙酰氨基酚（APAP）诱导的肝毒性）患者提供新的策略，这些疾病约占美国所有急性肝衰竭的一半。

DESCRIPTION (provided by applicant): The long term goal of this application is to 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, leading to strong transcriptional repression of Retinoid X Receptor 1 (RXR1). As RXR1 is the major heterodimer partner for most of the nuclear hormone receptors involved in numerous cellular metabolic processes, we hypothesize that repression of RXR1 and its regulated genes during viral infections can have strong impacts on host metabolisms especially drug metabolisms. We further suggest this 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, or acetaminophen (APAP)-induced hepatotoxicity, which accounts for about half of the acute liver failures in US. Interestingly, our preliminary studies indicate that innate immune responses to viral products can potentiate aspirin-induced but protect APAP-induced hepatotoxicity, which may explain why during viral infections patients are safer to use Tylenol than Aspirin. These results further suggest that, depending upon the nature of the drugs, viral infections may differentially affect the accumulation of the drug's intermediate metabolites, which could lead to opposite toxic effects on host tissues. In this application, we will first develop mouse models that mimic Reye's Syndrome and acetaminophen (APAP)-induced hepatotoxicity. We will then use these two opposite drug metabolism models as examples to determine how innate immune responses to viral infection could differentially alter stability or toxicity of different drugs. 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 an effective anti-viral response. We will further 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 virally 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. PUBLIC HEALTH RELEVANCE: Numerous diseases including metabolic diseases are associated with virus infections. On the other hand, many metabolic products and drugs can also affect our body's ability to defend against invading viruses. However, the molecular mechanisms responsible for such associations are not clear. We recently found a novel crosstalk between host immune response and metabolisms, which could explain not only viral associated liver diseases such as Reye's Syndrome but also how metabolic drugs can inhibit host response against viral infections. Further investigation on such crosstalk will provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases such as acetaminophen (APAP)-induced hepatotoxicity, which accounted for about half of all acute liver failures in America.