Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection.

IF 4 2区 医学 Q2 VIROLOGY
Roshan Ghimire, Rakshya Shrestha, Radhika Amaradhi, Lin Liu, Sunil More, Thota Ganesh, Alexandra K Ford, Rudragouda Channappanavar
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引用次数: 0

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced impaired antiviral immunity and excessive inflammatory responses cause lethal pneumonia. However, the in vivo roles of key pattern recognition receptors that elicit protective antiviral and fatal inflammatory responses, specifically in the lungs, are not well described. Coronaviruses possess single-stranded RNA genome that activates TLR7/8 to induce an antiviral interferon (IFN) and robust inflammatory cytokine response. Here, using wild-type and TLR7-deficient (TLR7-/-) mice infected with mouse-adapted SARS-CoV-2 (MA-CoV-2), we examined the role of TLR7 in the lung antiviral and inflammatory response and severe pneumonia. We showed that TLR7 deficiency significantly increased lung virus loads and morbidity/mortality, which correlated with reduced levels of type I IFNs (Ifna/b), type III IFNs (Ifnl), and IFN-stimulated genes (ISGs) in the lungs. A detailed evaluation of MA-CoV-2-infected lungs revealed increased neutrophil accumulation and lung pathology in TLR7-/- mice. We further showed that blocking type I IFN receptor (IFNAR) signaling enhanced SARS-CoV-2 replication in the lungs and caused severe lung pathology, leading to 100% mortality compared to infected control mice. Moreover, immunohistochemical assessment of the lungs revealed increased numbers of SARS-CoV-2 antigen-positive macrophages, pneumocytes, and bronchial epithelial cells in TLR7-/- and IFNAR-deficient mice compared to control mice. In summary, we conclusively demonstrated that despite TLR7-induced robust lung inflammation, TLR7-induced IFN/ISG responses suppress lung virus replication and pathology and provide protection against SARS-CoV-2-induced fatal pneumonia. Additionally, given the similar disease outcomes in control, TLR7-/-, and IFNAR-deficient MA-CoV-2-infected mice and coronavirus disease 2019 (COVID-19) patients, we propose that MA-CoV-2-infected mice constitute an excellent model for studying COVID-19.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is caused by a delicate balance between a strong antiviral and an exuberant inflammatory response. A robust antiviral immunity and regulated inflammation are protective, while a weak antiviral response and excessive inflammation are detrimental. However, the key host immune sensors that elicit protective antiviral and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge are poorly defined. Here, we examined the role of viral RNA-mediated TLR7 activation in the lung antiviral and inflammatory responses in SARS-CoV-2-infected mice. We demonstrate that TLR7 deficiency led to a high rate of morbidity and mortality, which correlated with an impaired antiviral interferon (IFN)-I/III response, enhanced lung virus replication, and severe lung pathology. Furthermore, we show that blocking IFN-I signaling using anti-IFN receptor antibody promoted SARS-CoV-2 replication in the lungs and caused severe disease. These results provide conclusive evidence that TLR7 and IFN-I receptor deficiencies lead to severe disease in mice, replicating clinical features observed in COVID-19 patients.

toll样受体7 (TLR7)介导的抗病毒反应保护小鼠免受致命的SARS-CoV-2感染。
严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)诱导的抗病毒免疫功能受损和过度炎症反应可导致致死性肺炎。然而,关键模式识别受体在体内的作用,引发保护性抗病毒和致命的炎症反应,特别是在肺部,并没有很好地描述。冠状病毒拥有单链RNA基因组,可激活TLR7/8,诱导抗病毒干扰素(IFN)和强烈的炎症细胞因子反应。在这里,我们使用野生型和TLR7缺陷(TLR7-/-)小鼠感染小鼠适应性SARS-CoV-2 (MA-CoV-2),研究TLR7在肺部抗病毒和炎症反应以及严重肺炎中的作用。我们发现,TLR7缺乏显著增加了肺部病毒载量和发病率/死亡率,这与肺中I型ifn (Ifna/b)、III型ifn (Ifnl)和ifn刺激基因(ISGs)水平的降低有关。对ma - cov -2感染的肺部的详细评估显示,TLR7-/-小鼠的中性粒细胞积累和肺部病理增加。我们进一步发现,阻断I型IFN受体(IFNAR)信号传导增强了SARS-CoV-2在肺部的复制,并导致严重的肺部病理,与感染对照小鼠相比,死亡率为100%。此外,肺免疫组织化学评估显示,与对照小鼠相比,TLR7-/-和ifnar缺陷小鼠的SARS-CoV-2抗原阳性巨噬细胞、肺细胞和支气管上皮细胞数量增加。总之,我们最终证明,尽管tlr7诱导了强烈的肺部炎症,但tlr7诱导的IFN/ISG反应抑制了肺部病毒的复制和病理,并提供了对sars - cov -2诱导的致命性肺炎的保护。此外,考虑到对照组、TLR7-/-和ifnar缺陷的ma - cov -2感染小鼠和2019冠状病毒病(COVID-19)患者的疾病结局相似,我们认为ma - cov -2感染小鼠是研究COVID-19的良好模型。2019年严重冠状病毒病(COVID-19)是由强大的抗病毒药物和旺盛的炎症反应之间的微妙平衡引起的。强大的抗病毒免疫和调节的炎症是保护性的,而弱的抗病毒反应和过度的炎症是有害的。然而,引发对严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)攻击的保护性抗病毒和炎症反应的关键宿主免疫传感器尚未明确定义。在这里,我们研究了病毒rna介导的TLR7激活在sars - cov -2感染小鼠肺部抗病毒和炎症反应中的作用。我们证明,TLR7缺陷导致高发病率和死亡率,这与抗病毒干扰素(IFN) i /III反应受损、肺部病毒复制增强和严重的肺部病理相关。此外,我们发现使用抗ifn受体抗体阻断IFN-I信号传导可促进SARS-CoV-2在肺部的复制并导致严重疾病。这些结果提供了确凿的证据,证明TLR7和IFN-I受体缺乏会导致小鼠出现严重疾病,并复制了在COVID-19患者中观察到的临床特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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