Laitinen Olli H, Svedin Emma, Kapell Sebastian, Nurminen Anssi, Hytönen Vesa P, Flodström-Tullberg Malin
BioMediTech, Finland and Fimlab Laboratories, University of Tampere, Tampere, Finland.
The Center for Infectious Medicine, Department of Medicine HS, Karolinska Institutet, Stockholm, Sweden.
Rev Med Virol. 2016 Jul;26(4):251-67. doi: 10.1002/rmv.1883. Epub 2016 May 4.
Enteroviruses are common human pathogens, and infections are particularly frequent in children. Severe infections can lead to a variety of diseases, including poliomyelitis, aseptic meningitis, myocarditis and neonatal sepsis. Enterovirus infections have also been implicated in asthmatic exacerbations and type 1 diabetes. The large disease spectrum of the closely related enteroviruses may be partially, but not fully, explained by differences in tissue tropism. The molecular mechanisms by which enteroviruses cause disease are poorly understood, but there is increasing evidence that the two enteroviral proteases, 2A(pro) and 3C(pro) , are important mediators of pathology. These proteases perform the post-translational proteolytic processing of the viral polyprotein, but they also cleave several host-cell proteins in order to promote the production of new virus particles, as well as to evade the cellular antiviral immune responses. Enterovirus-associated processing of cellular proteins may also contribute to pathology, as elegantly demonstrated by the 2A(pro) -mediated cleavage of dystrophin in cardiomyocytes contributing to Coxsackievirus-induced cardiomyopathy. It is likely that improved tools to identify targets for these proteases will reveal additional host protein substrates that can be linked to specific enterovirus-associated diseases. Here, we discuss the function of the enteroviral proteases in the virus replication cycle and review the current knowledge regarding how these proteases modulate the infected cell in order to favour virus replication, including ways to avoid detection by the immune system. We also highlight new possibilities for the identification of protease-specific cellular targets and thereby a way to discover novel mechanisms contributing to disease. Copyright © 2016 John Wiley & Sons, Ltd.
肠道病毒是常见的人类病原体，在儿童中感染尤为频繁。严重感染可导致多种疾病，包括小儿麻痹症、无菌性脑膜炎、心肌炎和新生儿败血症。肠道病毒感染还与哮喘加重和1型糖尿病有关。密切相关的肠道病毒所导致的广泛疾病谱，可能部分（但并非完全）可由组织嗜性差异来解释。人们对肠道病毒致病的分子机制了解甚少，但越来越多的证据表明，两种肠道病毒蛋白酶，即2A蛋白酶（2A(pro)）和3C蛋白酶（3C(pro)），是病理过程的重要介质。这些蛋白酶对病毒多聚蛋白进行翻译后蛋白水解加工，但它们也切割几种宿主细胞蛋白，以促进新病毒颗粒的产生，并逃避免疫细胞的抗病毒免疫反应。肠道病毒对细胞蛋白的加工也可能导致病理变化，如2A蛋白酶对心肌细胞中肌营养不良蛋白的切割导致柯萨奇病毒诱发的心肌病，这一过程就很好地证明了这一点。很可能，用于识别这些蛋白酶作用靶点的改进工具，将揭示更多可与特定肠道病毒相关疾病相联系的宿主蛋白底物。在此，我们讨论肠道病毒蛋白酶在病毒复制周期中的功能，并综述目前关于这些蛋白酶如何调节受感染细胞以利于病毒复制的知识，包括避免被免疫系统检测到的方式。我们还强调了识别蛋白酶特异性细胞靶点的新可能性，从而发现导致疾病的新机制。版权所有© 2016约翰威立父子有限公司。
