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Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. ​

文献信息 ​

DOI10.1016/j.cell.2020.04.004
PMID32333836
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2020
被引次数1346
关键词COVID-19，血管紧张素转化酶2，血管，人类类器官，肾脏
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
页码905-913.e7
期号181(4)
作者Vanessa Monteil, Hyesoo Kwon, Patricia Prado, Astrid Hagelkrüys, Reiner A Wimmer, Martin Stahl, Alexandra Leopoldi, Elena Garreta, Carmen Hurtado Del Pozo, Felipe Prosper, Juan Pablo Romero, Gerald Wirnsberger, Haibo Zhang, Arthur S Slutsky, Ryan Conder, Nuria Montserrat, Ali Mirazimi, Josef M Penninger

一句话小结 ​

本研究首次证明人源重组可溶性ACE2（hrsACE2）能够显著抑制SARS-CoV-2的生长，减少感染细胞中的病毒量1,000-5,000倍，且能有效阻止病毒感染工程化的人类器官。该发现为开发针对COVID-19的治疗方法提供了新的思路，强调了hrsACE2在早期感染阶段的潜在应用价值。

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COVID-19 · 血管紧张素转化酶2 · 血管 · 人类类器官 · 肾脏

摘要 ​

我们之前提供了首次的遗传证据，表明血管紧张素转化酶2（ACE2）是严重急性呼吸综合症冠状病毒（SARS-CoV）的关键受体，ACE2 保护肺部免受损伤，为因 SARS-CoV 感染导致的严重肺功能衰竭和死亡提供了分子解释。现在，ACE2 也被确认是 SARS-CoV-2 感染的关键受体，并且有人提出抑制这种相互作用可能用于治疗 COVID-19 患者。然而，目前尚不清楚人源重组可溶性 ACE2（hrsACE2）是否能够阻止 SARS-CoV-2 的生长。在这里，我们展示了临床等级的 hrsACE2 能够将 SARS-CoV-2 从 Vero 细胞的恢复减少 1,000-5,000 倍。而相应的小鼠 rsACE2 则没有任何效果。我们还展示了 SARS-CoV-2 可以直接感染工程化的人类血管类器官和人类肾脏类器官，这一过程可以被 hrsACE2 所抑制。这些数据表明，hrsACE2 可以显著阻止 SARS-CoV-2 感染的早期阶段。

英文摘要 ​

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

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主要研究问题 ​

  1. 使用hrsACE2对其他类型的病毒感染是否也有抑制作用？
  2. 在不同的工程化人类组织中，hrsACE2的抑制效果是否存在差异？
  3. 有哪些临床前或临床试验正在评估hrsACE2在COVID-19治疗中的有效性？
  4. 其他治疗策略（如疫苗或抗病毒药物）与hrsACE2的结合使用效果如何？
  5. 如何评估hrsACE2在临床应用中的安全性和有效性？

核心洞察 ​

研究背景和目的 ​

新型冠状病毒（SARS-CoV-2）引发的COVID-19疫情对全球公共卫生造成了重大影响。研究表明，血管紧张素转化酶2（ACE2）是SARS-CoV-2的主要受体，抑制该受体与病毒的结合可能为治疗COVID-19提供新策略。本研究旨在探讨临床级重组人ACE2（hrsACE2）对SARS-CoV-2感染的抑制作用。

主要方法/材料/实验设计 ​

本研究采用了多种实验设计，包括细胞培养、病毒感染和qRT-PCR检测等。

  1. 细胞和病毒模型：

    • 使用Vero E6细胞作为病毒感染模型。
    • 从COVID-19患者的样本中分离并培养SARS-CoV-2病毒。

  2. 重组人ACE2的制备：

    • 生产临床级的重组人ACE2（hrsACE2）并进行纯化。

  3. 感染实验：

    • Vero E6细胞与不同浓度的SARS-CoV-2病毒和hrsACE2共同培养。
    • 通过qRT-PCR检测病毒RNA的表达水平，以评估hrsACE2的抑制效果。

  4. 人类器官类器官模型：

    • 制备人类血管和肾脏类器官，研究hrsACE2对这些模型中SARS-CoV-2感染的影响。
Mermaid diagram

关键结果和发现 ​

  1. hrsACE2显著抑制SARS-CoV-2感染：

    • hrsACE2在体外实验中可将SARS-CoV-2的恢复量减少1000至5000倍。
    • 相较于小鼠ACE2（mrsACE2），hrsACE2对SARS-CoV-2的抑制效果显著。

  2. 人类血管和肾脏类器官感染：

    • SARS-CoV-2能够直接感染人类血管和肾脏类器官，且这种感染可以被hrsACE2显著抑制。

主要结论/意义/创新性 ​

本研究首次证明了临床级重组人ACE2（hrsACE2）在抑制SARS-CoV-2感染方面的有效性，表明其作为潜在治疗COVID-19的药物的前景。研究结果支持了hrsACE2作为一种新型干预手段，以保护肺部及其他受感染组织免受损伤。

研究局限性和未来方向 ​

  1. 研究局限性：

    • 本研究主要集中在感染早期阶段，未能探讨hrsACE2在疾病后期的作用。
    • 缺乏对肺类器官的研究，肺是COVID-19的主要靶器官。

  2. 未来方向：

    • 进一步研究hrsACE2在感染后期的效果。
    • 探索其在肺及其他器官类器官中的作用，以更全面地理解COVID-19的多脏器损伤机制。

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引用本文的文献 ​

  1. Reply to: "Reporting of all cardiac medications and their outcome in COVID-19". - Hao Cheng;Yan Wang;Gui-Qiang Wang - Journal of medical virology (2020)
  2. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. - Yung-Fang Tu;Chian-Shiu Chien;Aliaksandr A Yarmishyn;Yi-Ying Lin;Yung-Hung Luo;Yi-Tsung Lin;Wei-Yi Lai;De-Ming Yang;Shih-Jie Chou;Yi-Ping Yang;Mong-Lien Wang;Shih-Hwa Chiou - International journal of molecular sciences (2020)
  3. COVID-19 for the Cardiologist: Basic Virology, Epidemiology, Cardiac Manifestations, and Potential Therapeutic Strategies. - Deepak Atri;Hasan K Siddiqi;Joshua P Lang;Victor Nauffal;David A Morrow;Erin A Bohula - JACC. Basic to translational science (2020)
  4. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. - Yanwei Li;Wei Zhou;Li Yang;Ran You - Pharmacological research (2020)
  5. COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities. - Bonnie Ky;Douglas L Mann - JACC. Basic to translational science (2020)
  6. COVID-19 Clinical Trials: A Primer for the Cardiovascular and Cardio-Oncology Communities. - Bonnie Ky;Douglas L Mann - JACC. CardioOncology (2020)
  7. Endothelial cell infection and endotheliitis in COVID-19. - Zsuzsanna Varga;Andreas J Flammer;Peter Steiger;Martina Haberecker;Rea Andermatt;Annelies S Zinkernagel;Mandeep R Mehra;Reto A Schuepbach;Frank Ruschitzka;Holger Moch - Lancet (London, England) (2020)
  8. SARS-Cov-2 (human) and COVID-19: Primer 2020. - Gayatri Ramakrishna;Pradeep Kumar;Savera Aggarwal;Mojahidul Islam;Ravinder Singh;Rakesh K Jagdish;Nirupma Trehanpati - Hepatology international (2020)
  9. A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance. - Krishna Sriram;Paul A Insel - British journal of pharmacology (2020)
  10. Current status of potential therapeutic candidates for the COVID-19 crisis. - Jiancheng Zhang;Bing Xie;Kenji Hashimoto - Brain, behavior, and immunity (2020)

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