Department of Immunobiology, Yale School of Medicine, New Haven, CT.
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT.
J Exp Med. 2022 Jan 3;219(1). doi: 10.1084/jem.20211818. Epub 2021 Nov 10.
As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.
随着 SARS-CoV-2 在全球范围内继续导致发病率和死亡率，迫切需要开发有效的医疗对策。在这里，我们评估了一种最小的 RIG-I 激动剂，茎环 RNA 14（SLR14）在病毒控制、疾病预防、感染后治疗以及 SARS-CoV-2 感染小鼠模型中的交叉变体保护方面的抗病毒能力。单次剂量的 SLR14 以 I 型干扰素（IFN-I）依赖性方式阻止了下呼吸道的病毒感染和严重疾病的发展。SLR14 对致死性 SARS-CoV-2 感染表现出显著的预防保护能力，并作为治疗剂保留了相当大的疗效。在携带慢性 SARS-CoV-2 感染的免疫功能低下的小鼠中，SLR14 在没有适应性免疫系统的情况下引发了近乎杀菌的先天免疫。在关注的变异体（VOCs）感染的情况下，SLR14 提供了对新兴 VOCs 的广泛保护。这些发现表明 SLR14 作为一种宿主定向的、广谱抗病毒药物，具有早期暴露后治疗和治疗慢性感染免疫抑制患者的治疗潜力。
