Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Virol. 2021 May 24;95(12). doi: 10.1128/JVI.00490-21.
The COVID-19 pandemic poses a serious global health threat. The rapid global spread of SARS-CoV-2 highlights an urgent need to develop effective therapeutics for blocking SARS-CoV-2 infection and spread. imulator of terferon enes (STING) is a chief element in host antiviral defense pathways. In this study, we examined the impact of the STING signaling pathway on coronavirus infection using the human coronavirus OC43 (HCoV-OC43) model. We found that HCoV-OC43 infection did not stimulate the STING signaling pathway, but the activation of STING signaling effectively inhibits HCoV-OC43 infection to a much greater extent than that of type I interferons (IFNs). We also discovered that IRF3, the key STING downstream innate immune effector, is essential for this anticoronavirus activity. In addition, we found that the amidobenzimidazole (ABZI)-based human STING agonist diABZI robustly blocks the infection of not only HCoV-OC43 but also SARS-CoV-2. Therefore, our study identifies the STING signaling pathway as a potential therapeutic target that could be exploited for developing broad-spectrum antiviral therapeutics against multiple coronavirus strains in order to face the challenge of future coronavirus outbreaks. The highly infectious and lethal SARS-CoV-2 is posing an unprecedented threat to public health. Other coronaviruses are likely to jump from a nonhuman animal to humans in the future. Novel broad-spectrum antiviral therapeutics are therefore needed to control known pathogenic coronaviruses such as SARS-CoV-2 and its newly mutated variants, as well as future coronavirus outbreaks. STING signaling is a well-established host defense pathway, but its role in coronavirus infection remains unclear. In the present study, we found that activation of the STING signaling pathway robustly inhibits infection of HCoV-OC43 and SARS-CoV-2. These results identified the STING pathway as a novel target for controlling the spread of known pathogenic coronaviruses, as well as emerging coronavirus outbreaks.
新型冠状病毒肺炎疫情构成严重的全球健康威胁。SARS-CoV-2 的迅速在全球范围内传播突出表明迫切需要开发有效的治疗方法来阻断 SARS-CoV-2 感染和传播。干扰素基因刺激物（STING）是宿主抗病毒防御途径的主要组成部分。在这项研究中，我们使用人冠状病毒 OC43（HCoV-OC43）模型研究了 STING 信号通路对冠状病毒感染的影响。我们发现 HCoV-OC43 感染不会刺激 STING 信号通路，但 STING 信号的激活可更有效地抑制 HCoV-OC43 感染，其抑制程度远大于 I 型干扰素（IFN）。我们还发现，STING 的关键下游先天免疫效应因子 IRF3 对于这种抗冠状病毒活性至关重要。此外，我们发现基于 amidobenzimidazole（ABZI）的人 STING 激动剂 diABZI 可有效阻止 HCoV-OC43 和 SARS-CoV-2 的感染。因此，我们的研究将 STING 信号通路确定为一种潜在的治疗靶标，可用于开发针对多种冠状病毒株的广谱抗病毒治疗药物，以应对未来冠状病毒爆发的挑战。高传染性和高致死性的 SARS-CoV-2 对公共卫生构成了前所未有的威胁。未来其他冠状病毒很可能从非人类动物传播到人类。因此，需要新型广谱抗病毒治疗药物来控制已知的致病性冠状病毒，如 SARS-CoV-2 及其新突变株，以及未来的冠状病毒爆发。STING 信号是一种成熟的宿主防御途径，但它在冠状病毒感染中的作用尚不清楚。在本研究中，我们发现 STING 信号通路的激活可有效抑制 HCoV-OC43 和 SARS-CoV-2 的感染。这些结果确定了 STING 途径是控制已知致病性冠状病毒以及新出现的冠状病毒爆发的新靶点。
