Picornavirus-initiated inflamation: novel parallels from Drosophila

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（包括扩张性心肌病），约占所有心脏移植病例的一半。特别是，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与病毒性心肌炎之间的联系已得到证实，但人们对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RNA解旋酶RLRs （rig - i样受体）检测细胞质中小核糖核酸病毒的存在。本提案的主要目的是确定RLRs如何激活NF-？B触发小核糖核酸病毒感染后的炎症反应。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。我们提出，小冠病毒激活rlr，触发一种新的细胞质信号复合体的形成，我们称之为FADDosome。我们之前的研究表明，FADDosome（包括FADD、TRADD、RIP1和选择性半胱天冬酶分子）特异性地激活NF-？但FADDosome调控NF-？B未知。FADD-based 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）的先天免疫途径有很强的相似之处。基于这些令人兴奋的相似性，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NF-？FADDosome对rlr的激活。在本提案中，我们将(1)与已建立的IMD途径进行比较，以确定FADDosome如何激活NF-？(2)检验RLR-NF-?的可行性。B抑制作为小核糖核酸病毒驱动的心肌炎的治疗途径。

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.