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

IRF3 和 RXRa 串扰在宿主对病毒感染的反应中的作用

• 批准号: 8481502
• 负责人: GENHONG CHENG
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481502
• 关键词: Accounting; Acetaminophen; Acute Liver Failure; Affect; Agonist; Americas; Antiviral Agents; Antiviral Response; Aspirin; Biological; Cells; Cellular Metabolic Process; Chemosensitization; Child; Cytochrome P450; Data; Disease; Family member; Gene Targeting; Genes; Goals; Health; Hepatocyte; Hepatotoxicity; Hormones; Host Defense; Immune; Immune response; Infection; Interferon Type I; Invaded; Investigation; Knockout Mice; Lead; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Nature; Nuclear; Nuclear Hormone Receptors; Nuclear Receptor Gene; Nuclear Receptors; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Proteomics; RXR; Repression; Reye Syndrome; Role; Signal Pathway; Signaling Molecule; Tissue Transplantation; Tissues; Toll-like receptors; Toxic effect; Tylenol; Vesicular stomatitis Indiana virus; Viral; Viral Pathogenesis; Virus; Virus Diseases; cell type; drug metabolism; drug modification; gene repression; human IRF3 protein; immunoregulation; interferon regulatory factor-3; liver injury; mouse model; novel; novel strategies; pathogen; prevent; programs

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.

描述（由申请人提供）：本申请的长期目标是阐明先天免疫反应和核激素受体之间的串扰在宿主防御感染和病原体相关代谢疾病中的机制和生物学意义。我们实验室的初步数据发现，在对病毒产物刺激或病毒感染的先天免疫反应过程中诱导出一种新的干扰素调节因子 3 (IRF3) 依赖性但独立于 I 型干扰素的途径，从而导致类视黄醇 X 受体 1 (RXR1) 的强烈转录抑制。由于 RXR1 是参与众多细胞代谢过程的大多数核激素受体的主要异二聚体伴侣，我们假设在病毒感染期间抑制 RXR1 及其调节基因会对宿主代谢尤其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，例如雷氏综合症，这是一种肝毒性疾病，当儿童在病毒感染的情况下服用阿司匹林时发生，或对乙酰氨基酚（APAP）引起的肝毒性，这约占美国一半的急性肝功能衰竭。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但保护 APAP 诱导的肝毒性，这可能解释了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地影响药物中间代谢物的积累，这可能导致对宿主组织产生相反的毒性作用。在此应用中，我们将首先开发模拟雷氏综合症和对乙酰氨基酚 (APAP) 诱导的肝毒性的小鼠模型。然后，我们将使用这两种相反的药物代谢模型作为示例，以确定对病毒感染的先天免疫反应如何不同地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，我们还假设先天免疫反应对核激素受体的抑制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反应的影响，以确定先天免疫反应对核激素受体的抑制对于宿主正确防御病毒感染是否是必要的。我们相信，对先天免疫反应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了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的新策略患有病毒感染及其相关代谢性疾病的患者。

项目成果

Integrating computational modeling and functional assays to decipher the structure-function relationship of influenza virus PB1 protein.

整合计算模型和功能测定来破译流感病毒PB1蛋白的结构-功能关系

• DOI: 10.1038/srep07192
• 发表时间: 2014-11-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Li C;Wu A;Peng Y;Wang J;Guo Y;Chen Z;Zhang H;Wang Y;Dong J;Wang L;Qin FX;Cheng G;Deng T;Jiang T
• 通讯作者: Jiang T