SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801,Nature

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SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801
Nature ( IF 50.5 ) Pub Date : 2021-02-09 , DOI: 10.1038/s41586-021-03312-w
Angela Wahl _{1,

2,

3} , Lisa E Gralinski ₄ , Claire E Johnson _{1,

2,

3} , Wenbo Yao _{1,

2,

3} , Martina Kovarova _{1,

2,

3} , Kenneth H Dinnon _{4,

5} , Hongwei Liu _{6,

7} , Victoria J Madden ₈ , Halina M Krzystek _{6,

7} , Chandrav De _{1,

2,

3} , Kristen K White ₈ , Kendra Gully ₄ , Alexandra Schäfer ₄ , Tanzila Zaman _{6,

7} , Sarah R Leist ₄ , Paul O Grant _{6,

7} , Gregory R Bluemling _{9,

10} , Alexander A Kolykhalov _{9,

10} , Michael G Natchus ₁₀ , Frederic B Askin ₁₁ , George Painter _{9,

10,

12} , Edward P Browne _{2,

3,

5,

13} , Corbin D Jones _{6,

7} , Raymond J Pickles _{5,

14} , Ralph S Baric _{4,

5,

15} , J Victor Garcia _{1,

2,

3}

Affiliation

International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Microscopy Services Laboratory, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Emory Institute of Drug Development (EIDD), Emory University, Atlanta, GA, USA.
Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA, USA.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA.
UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marsico Lung Institute, University of North Carolina at Chapel, Chapel Hill, NC, USA.
Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

All coronaviruses known to have recently emerged as human pathogens probably originated in bats¹. Here we use a single experimental platform based on immunodeficient mice implanted with human lung tissue (hereafter, human lung-only mice (LoM)) to demonstrate the efficient in vivo replication of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as two endogenous SARS-like bat coronaviruses that show potential for emergence as human pathogens. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats contain endogenous coronaviruses that are capable of direct transmission to humans. Our detailed analysis of in vivo infection with SARS-CoV-2 in human lung tissue from LoM showed a predominant infection of human lung epithelial cells, including type-2 pneumocytes that are present in alveoli and ciliated airway cells. Acute infection with SARS-CoV-2 was highly cytopathic and induced a robust and sustained type-I interferon and inflammatory cytokine and chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for SARS-CoV-2 infection. Our results show that therapeutic and prophylactic administration of EIDD-2801—an oral broad-spectrum antiviral agent that is currently in phase II/III clinical trials—markedly inhibited SARS-CoV-2 replication in vivo, and thus has considerable potential for the prevention and treatment of COVID-19.

中文翻译：

EIDD-2801有效治疗和预防SARS-CoV-2感染

所有已知最近作为人类病原体出现的冠状病毒都可能起源于蝙蝠¹. 在这里，我们使用基于植入人肺组织的免疫缺陷小鼠（以下简称人肺小鼠（LoM））的单一实验平台来证明中东呼吸系统严重急性呼吸综合征冠状病毒（SARS-CoV）在体内的有效复制综合症冠状病毒 (MERS-CoV) 和严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2)，以及两种内源性类 SARS 蝙蝠冠状病毒，它们显示出可能成为人类病原体。该模型中的病毒复制发生在真正的人肺组织中，不需要病毒或宿主的任何类型的适应。我们的研究结果表明，蝙蝠含有能够直接传播给人类的内源性冠状病毒。我们对来自 LoM 的人肺组织中 SARS-CoV-2 体内感染的详细分析显示，人肺上皮细胞主要感染人肺上皮细胞，包括存在于肺泡和纤毛气道细胞中的 2 型肺细胞。SARS-CoV-2 的急性感染具有高度细胞病变性，并诱导强烈且持续的 I 型干扰素和炎性细胞因子和趋化因子反应。最后，我们评估了针对 SARS-CoV-2 感染的治疗和暴露前预防策略。我们的研究结果表明，EIDD-2801（一种目前处于 II/III 期临床试验的口服广谱抗病毒药物）的治疗性和预防性给药显着抑制了 SARS-CoV-2 在体内的复制，因此具有相当大的预防潜力和 COVID-19 的治疗。包括存在于肺泡和纤毛气道细胞中的 2 型肺细胞。SARS-CoV-2 的急性感染具有高度细胞病变性，并诱导强烈且持续的 I 型干扰素和炎性细胞因子和趋化因子反应。最后，我们评估了针对 SARS-CoV-2 感染的治疗和暴露前预防策略。我们的研究结果表明，EIDD-2801（一种目前处于 II/III 期临床试验的口服广谱抗病毒药物）的治疗性和预防性给药显着抑制了 SARS-CoV-2 在体内的复制，因此具有相当大的预防潜力和 COVID-19 的治疗。包括存在于肺泡和纤毛气道细胞中的 2 型肺细胞。SARS-CoV-2 的急性感染具有高度细胞病变性，并诱导强烈且持续的 I 型干扰素和炎性细胞因子和趋化因子反应。最后，我们评估了针对 SARS-CoV-2 感染的治疗和暴露前预防策略。我们的研究结果表明，EIDD-2801（一种目前处于 II/III 期临床试验的口服广谱抗病毒药物）的治疗性和预防性给药显着抑制了 SARS-CoV-2 在体内的复制，因此具有相当大的预防潜力和 COVID-19 的治疗。我们评估了针对 SARS-CoV-2 感染的治疗和暴露前预防策略。我们的研究结果表明，EIDD-2801（一种目前处于 II/III 期临床试验的口服广谱抗病毒药物）的治疗性和预防性给药显着抑制了 SARS-CoV-2 在体内的复制，因此具有相当大的预防潜力和 COVID-19 的治疗。我们评估了针对 SARS-CoV-2 感染的治疗和暴露前预防策略。我们的研究结果表明，EIDD-2801（一种目前处于 II/III 期临床试验的口服广谱抗病毒药物）的治疗性和预防性给药显着抑制了 SARS-CoV-2 在体内的复制，因此具有相当大的预防潜力和 COVID-19 的治疗。

更新日期：2021-02-09

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