PDF(Pubmed)
Abstract：
Following the successful control of poliovirus, the re-emergence of respiratory enterovirus D68 (EV-D68), a prominent non-polio enterovirus, has become a serious public health concern worldwide. Host innate immune responses are the primary defense against EV-D68 invasion; however, the mechanism underlying viral evasion of the antiviral activity of interferons (IFN) remains unclear. In this study, we found that EV-D68 inhibited type I IFN signaling by cleaving signal transducer and activator of transcription 1 (STAT1), a crucial factor in cellular responses to interferons and other cytokines. We observed that the prototype and circulating EV-D68 strains conserved their ability to induce STAT1 cleavage and attenuate IFN signal transduction. Further investigation revealed that EV-D68 3C protease cleaves STAT1 at the 131Q residue. Interestingly, not all enterovirus-encoded 3C proteases exhibited this ability. EV-D68 and poliovirus 3C proteases efficiently induced STAT1 cleavage; whereas, 3C proteases from EV-A71, coxsackievirus A16, and echoviruses did not. STAT1 cleavage also abolished the nuclear translocation capacity of STAT1 in response to IFN stimulation to activate downstream signaling elements. Overall, these results suggest that STAT1, targeted by viral protease 3C, is utilized by EV-D68 to subvert the host\'s innate immune response.IMPORTANCEEnterovirus D68 (EV-D68) has significantly transformed over the past decade, evolving from a rare pathogen to a potential pandemic pathogen. The interferon (IFN) signaling pathway is an important defense mechanism and therapeutic target for the host to resist viral invasion. Previous studies have reported that the EV-D68 virus blocks or weakens immune recognition and IFN production in host cells through diverse strategies; however, the mechanisms of EV-D68 resistance to IFN signaling have not been fully elucidated. Our study revealed that EV-D68 relies on its own encoded protease, 3C, to directly cleave signal transducer and activator of transcription 1 (STAT1), a pivotal transduction component in the IFN signaling pathway, disrupting the IFN-mediated antiviral response. Previous studies on human enteroviruses have not documented direct cleavage of the STAT1 protein to evade cellular immune defenses. However, not all enteroviral 3C proteins can cleave STAT1. These findings highlight the diverse evolutionary strategies different human enteroviruses employ to evade host immunity.
摘要：
在成功控制脊髓灰质炎病毒后，呼吸道肠道病毒D68（EV-D68）的重新出现，一种突出的非脊髓灰质炎肠道病毒，已成为全球严重的公共卫生问题。宿主先天性免疫反应是抵御EV-D68入侵的主要防御;然而，病毒逃避干扰素（IFN）抗病毒活性的潜在机制尚不清楚。在这项研究中,我们发现EV-D68通过切割信号转导和转录激活因子1（STAT1）抑制I型IFN信号，细胞对干扰素和其他细胞因子反应的关键因素。我们观察到原型和循环EV-D68菌株保留了它们诱导STAT1裂解和减弱IFN信号转导的能力。进一步的研究显示,EV-D683C蛋白酶在131Q残基处切割STAT1。有趣的是,并非所有肠道病毒编码的3C蛋白酶都表现出这种能力。EV-D68和脊髓灰质炎病毒3C蛋白酶有效诱导STAT1裂解；然而，来自EV-A71，柯萨奇病毒A16和回声病毒的3C蛋白酶没有。STAT1裂解还消除了STAT1响应于IFN刺激激活下游信号元件的核易位能力。总的来说,这些结果表明，由病毒蛋白酶3C靶向的STAT1，EV-D68利用它来颠覆宿主的先天免疫反应。IMPORTANCE肠病毒D68（EV-D68）在过去十年中发生了重大变化，从一种罕见的病原体演变为一种潜在的大流行病原体。干扰素(IFN)信号通路是宿主抵抗病毒侵袭的重要防御机制和治疗靶点。以前的研究报道，EV-D68病毒通过不同的策略阻断或削弱宿主细胞中的免疫识别和IFN的产生；然而，EV-D68对IFN信号传导的抗性机制尚未完全阐明。我们的研究表明，EV-D68依赖于自己编码的蛋白酶，3C,直接切割信号转导和转录激活因子1（STAT1），IFN信号通路中的关键转导成分，破坏IFN介导的抗病毒反应。以前对人类肠道病毒的研究没有记载直接裂解STAT1蛋白以逃避细胞免疫防御。然而,并非所有的肠道病毒3C蛋白都能裂解STAT1。这些发现强调了不同人类肠道病毒用来逃避宿主免疫的不同进化策略。
