Picornavirus-initiated inflamation: novel parallels from Drosophila

描述(申请人提供)：病毒感染被认为是心肌炎(或心肌炎)的主要原因，慢性心肌炎通常会导致更严重的心脏疾病(包括扩张性心肌病)，约占所有心脏移植病例的一半。特别是，微小核糖核酸病毒，如B型柯萨奇病毒，被认为是病毒性心肌炎的典型病原体。虽然微小核糖核酸病毒感染和病毒性心肌炎之间的联系已经得到了很好的证实，但对微小核糖核酸病毒感染心肌细胞引发炎症的分子机制知之甚少。心肌细胞通过被称为RIG-I样受体的RNA解旋酶来检测细胞质中微小核糖核酸病毒的存在。这项建议的主要目的是确定RLRs如何激活核因子-βB以触发微小核糖核酸病毒感染后的炎症反应。明确核因子-B调节的促炎信号产生的机制将为合理的治疗策略提供依据，从而改变有益的抗病毒反应和有害的心肌炎反应之间的平衡。我们认为，微冠状病毒激活RLR以触发一种新的细胞质信号复合体的形成，我们称之为FADDosome。我们以前的工作表明，FADDosome(包括FADD、Tradd、RIP1和Sect caspase)在病毒感染后特异性地激活NF-βB，但FADDosome调节NF-βB的机制尚不清楚。基于FADD的核因子？B的激活在脊椎动物生物学中似乎是独一无二的，但与果蝇中一种被低估的先天性免疫途径有很强的相似性，称为免疫缺陷(IMD)。基于这些具有挑衅性的相似性，我们假设果蝇IMD样信号模块在脊椎动物中是保守的，它介导FADDosome对RLRs的反应激活NF-？B。在这项提案中，我们将(1)从已建立的IMD途径中进行比较，以确定FADDosome如何在微小RNA病毒刺激RLR后激活NF-？B，以及(2)测试RLR-NF-？B抑制作为微小RNA病毒驱动的心肌炎的治疗途径的可行性。

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.