Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway
Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway
复制标题
DOI：
10.1128/jvi.01913-17
复制
发表时间：
2018-03-01
影响因子：
5.4
通讯作者：
DeFilippis, Victor
中科院分区：
文献类型：
--
作者：
Gall, Bryan;Pryke, Kara;DeFilippis, Victor
I型干扰素系统是一种重要的先天免疫反应，通过干扰素诱导的效应蛋白的分子作用，使细胞抵抗病毒的生长。干扰素介导的细胞状态抑制多种不同类型的病毒的生长，包括那些已知的致病性以及潜在的新兴病原体。因此，靶向药物激活干扰素反应可能代表一种新的治疗策略，以防止感染或临床上有影响力的病毒的传播。有鉴于此，我们采用了高通量筛选来识别能够渗透到细胞并激活干扰素依赖的信号过程的小分子。在这里，我们报道了一种新的能够诱导人细胞分泌干扰素的化合物N-(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1，3，4-oxadiazol-2-yl]磺酰-2-苯乙酰胺(简称C11)的鉴定和性质。使用基于反向遗传学的功能丧失分析，我们表明C11激活I型干扰素反应的方式需要接头蛋白刺，但不需要替代接头MAVS和TRIF。重要的是，用C11处理细胞产生了一种细胞状态，有效地阻止了多种新出现的甲型病毒的复制，包括基孔肯雅病毒、罗斯河病毒、委内瑞拉马脑炎病毒、马亚罗病毒和O‘nyong-Nyong病毒。C11的抗病毒作用随后在缺乏STING或I型干扰素受体的细胞中被取消，这表明它们至少主要是通过STING介导的干扰素分泌和随后的自分泌/旁分泌信号来介导的。这项工作还可以表征先天免疫信号适配器和干扰素介导的反应的不同抗病毒作用，并确定MAV在细胞对甲病毒感染的抵抗力中至关重要。重要的是，由于新出现的节肢动物传播病毒，如基孔肯雅病毒，缺乏FDA批准的治疗方法和疫苗，重要的是更好地了解导致病毒清除的信号通路。在这里，我们表明C11治疗使人类细胞对其中一些病毒的复制产生困难，这支持了它在增加我们对建立宿主感染所需的免疫反应和病毒发病机制的理解方面的价值。我们还表明，C11依赖于通过STING的信号来产生抗病毒的I型干扰素，这进一步支持了它作为治疗药物或研究工具的潜力。
The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFN-induced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N-(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse genetics-based loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection.IMPORTANCE Due to the increase in emerging arthropod-borne viruses, such as chikungunya virus, that lack FDA-approved therapeutics and vaccines, it is important to better understand the signaling pathways that lead to clearance of virus. Here we show that C11 treatment makes human cells refractory to replication of a number of these viruses, which supports its value in increasing our understanding of the immune response and viral pathogenesis required to establish host infection. We also show that C11 depends on signaling through STING to produce antiviral type I interferon, which further supports its potential as a therapeutic drug or research tool.