Ubiquitin-Like Protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in Host Defense Against Heart Failure in a Mouse Model of Virus-Induced Cardiomyopathy
Ubiquitin-Like Protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in Host Defense Against Heart Failure in a Mouse Model of Virus-Induced Cardiomyopathy
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DOI：
10.1161/circulationaha.114.009847
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发表时间：
2014-10-28
期刊：
影响因子：
37.8
通讯作者：
Voigt, Antje
中科院分区：
文献类型：
--
作者：
Rahnefeld, Anna;Klingel, Karin;Voigt, Antje
背景-炎症性心肌病的常见致病因素包括嗜心病毒，如柯萨奇病毒B3(CVB3)。在这里，我们研究了泛素样修饰物干扰素刺激基因15 kDa(ISG15)在病毒性心肌病发病机制中的作用。方法和结果-在CVB3感染的小鼠中，ISG15缺乏蛋白质修饰伴随着心肌炎的严重恶化以及死亡率和心力衰竭的显著增加。我们发现，心肌细胞中的ISG15对病毒复制有显著的抑制作用。在没有完整的ISG15系统的情况下，病毒滴度在感染后第8天显著升高，病毒RNA在感染后第28天在ISG15(-/-)小鼠中持续存在。在CVB3感染中去除ISG15蛋白修饰系统使小鼠容易患上长期疾病，胶原纤维沉积，所有这些都导致炎症性心肌病。我们发现ISG15作为心肌细胞固有免疫的一部分，并且没有检测到ISG15修饰对细胞免疫反应的显著影响。CVB3 2 A蛋白水解酶的ISG15修饰抵消了CVB3诱导的宿主细胞真核翻译起始因子eIF4G在心肌细胞中的裂解，从而抵消了CVB3感染中宿主细胞翻译的关闭。我们证明了ISG15抑制了人心肌细胞的感染性病毒产量和病毒性心肌病患者ISG15的诱导。结论-ISG15结合系统代表了心肌细胞中一种关键的固有反应机制，以对抗入侵病原体，限制炎症性心肌病，心力衰竭和死亡。干扰ISG15系统可能是治疗病毒性心肌病的一种新方法。
Background-Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy.Methods and Results-In CVB3-infected mice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15(-/-) mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3 infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3 infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy.Conclusions-The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy.