Picornavirus-initiated inflamation: novel parallels from Drosophila

小核糖核酸病毒引发的炎症：果蝇的新相似之处

• 批准号: 8608479
• 负责人: SIDDHARTH BALACHANDRAN
• 金额: $ 26.78万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608479
• 关键词: Accounting; Acute; Adaptor Signaling Protein; Affect; Antiviral Agents; Antiviral Response; Apoptotic; Boxing; Cardiac Myocytes; Caspase; Caspase-1; Chronic; Cleaved cell; Complex; Congestive Heart Failure; Coxsackie B Viruses; Cytoplasm; Data; Development; Dilated Cardiomyopathy; Disease; Drosophila genus; Equilibrium; Family Picornaviridae; Goals; Heart Diseases; Heart Transplantation; Human Virus; Immune; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Lead; Left; Link; Mediating; Modeling; Molecular; Mus; Myocardial; Myocarditis; Myocardium; Nature; Pathway interactions; Peptides; Picornaviridae Infections; RNA Helicase; Reaction; Receptor Signaling; Research; Signal Transduction; TRADD gene; Testing; Text; Therapeutic; Vertebrate Biology; Vertebrates; Viral; Virus; Virus Diseases; Work; base; caspase-8; in vivo; microbial; novel; prevent; programs; public health relevance; receptor; research study; response; transcription factor; virus infection mechanism

DESCRIPTION (provided by applicant): Virus infections are recognized as a major cause of myocarditis (or inflammation of the heart muscle), and chronic myocarditis often leads to more severe cardiac disease (including dilated cardiomyopathy) that accounts for approximately half of all heart transplant cases. In particular, picornaviruses such as type B coxsackieviruses are considered the prototypic causative agents of viral myocarditis. While the link between picornavirus infections and viral myocarditis has been well-established, little is known about the molecular mechanisms by which a picornavirus infection of the cardiomyocyte initiates inflammation. Cardiomyocytes detect the presence of a picornavirus in the cytoplasm via RNA helicases called RLRs (RIG-I-like receptors). The primary objective of this proposal is to determine how RLRs activate NF-?B to trigger inflammatory responses following picornavirus infection. Identifying the mechanisms by which the NF-?B-regulated pro-inflammatory signal is generated will inform rational therapeutic strategies to alter the balance between a beneficial antiviral response and a deleterious myocardial inflammatory reaction. We propose that picronaviruses activate RLRs to trigger formation of a novel cytoplasmic signaling complex that we call the FADDosome. Our previous work has shown that the FADDosome (comprising the molecules FADD, TRADD, RIP1 and select caspases) specifically activates NF-?B following virus infection, but the mechanism by which the FADDosome regulates NF-?B is unknown. FADD-based NF-?B activation appears to be unique in vertebrate biology, but shares strong parallels with an under-appreciated innate immune pathway in Drosophila called Immune Deficient (IMD). Based on these provocative similarities, we hypothesize that a Drosophila IMD-like signaling module is conserved in vertebrates where it mediates NF-?B activation by the FADDosome in response to RLRs. In this proposal, we will (1) draw comparisons from the established IMD pathway to identify how the FADDosome activates NF-?B following stimulation of RLRs by picornaviruses, and (2) test the feasibility of RLR-NF-?B inhibition as a therapeutic avenue for picornavirus-driven myocarditis.

描述（由申请人提供）：病毒感染被认为是心肌炎（或心肌炎症）的主要原因，慢性心肌炎通常导致更严重的心脏疾病（包括扩张型心肌病），约占所有心脏移植病例的一半。特别地，小核糖核酸病毒如B型柯萨奇病毒被认为是病毒性心肌炎的原型病原体。虽然小核糖核酸病毒感染和病毒性心肌炎之间的联系已经很好地建立，但对心肌细胞的小核糖核酸病毒感染引发炎症的分子机制知之甚少。心肌细胞通过称为RLR（RIG-I样受体）的RNA解旋酶检测细胞质中小核糖核酸病毒的存在。这项建议的主要目标是确定如何RLRs激活NF-？B在小核糖核酸病毒感染后引发炎症反应。确定NF-？B调节的促炎信号的产生将为合理的治疗策略提供信息，以改变有益的抗病毒反应和有害的心肌炎症反应之间的平衡。 我们认为，picronaviruses激活RLR触发形成一种新的细胞质信号复合物，我们称之为FADDosome。我们以前的工作表明，FADDosome（包括分子FADD，TRADD，RIP 1和选择半胱天冬酶）特异性激活NF-？B病毒感染后，但FADDosome调节NF-？B未知。基于FADD的NF-？B激活在脊椎动物生物学中似乎是独特的，但与果蝇中被称为免疫缺陷（IMD）的未被充分认识的先天免疫途径有很强的相似之处。基于这些挑衅的相似性，我们假设果蝇IMD样信号模块是保守的脊椎动物，它介导NF-？FADDosome响应于RLR激活B。在这个提议中，我们将（1）从已建立的IMD途径进行比较，以确定FADDosome如何激活NF-？B，以及（2）测试RLR-NF-？B抑制作为小RNA病毒驱动的心肌炎的治疗途径。