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

Literature Information ​

DOI10.1016/j.cell.2020.04.004
PMID32333836
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2020
Times Cited1346
KeywordsCOVID-19, angiotensin converting enzyme 2, blood vessels, human organoids, kidney
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages905-913.e7
Issue181(4)
AuthorsVanessa 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

TL;DR ​

This study provides evidence that human recombinant soluble ACE2 (hrsACE2) significantly inhibits SARS-CoV-2 growth in vitro, reducing viral recovery from Vero cells by 1,000-5,000 times, while mouse ACE2 showed no effect. The findings suggest that hrsACE2 could be a promising therapeutic approach for treating COVID-19 by blocking early stages of infection in human organoids.

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COVID-19 · angiotensin converting enzyme 2 · blood vessels · human organoids · kidney

Abstract ​

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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Primary Questions Addressed ​

  1. What are the potential mechanisms by which soluble human ACE2 could inhibit SARS-CoV-2 infections in different types of human tissues?
  2. How does the efficacy of clinical-grade hrsACE2 compare to other therapeutic agents currently being explored for COVID-19 treatment?
  3. What are the implications of using engineered human organoids for studying SARS-CoV-2 infections and testing potential treatments?
  4. Could the findings regarding hrsACE2 lead to new vaccine strategies or preventative measures against SARS-CoV-2?
  5. What are the safety and ethical considerations in using recombinant proteins like hrsACE2 in clinical settings for COVID-19 patients?

Key Findings ​

Research Background and Purpose ​

The study investigates the role of soluble human angiotensin-converting enzyme 2 (hrsACE2) as a potential therapeutic agent against SARS-CoV-2, the virus responsible for COVID-19. ACE2 is known to be the primary receptor for SARS-CoV-2, and inhibiting this interaction could provide a novel treatment strategy for COVID-19, particularly to mitigate severe lung injuries and multi-organ failure associated with the disease.

Main Methods/Materials/Experimental Design ​

The study utilized several experimental approaches to evaluate the efficacy of hrsACE2 in inhibiting SARS-CoV-2 infections in vitro:

  1. Viral Isolation and Characterization:

    • SARS-CoV-2 was isolated from a nasopharyngeal sample of a COVID-19 patient and cultured on Vero E6 cells.
    • The virus was characterized using next-generation sequencing and phylogenetic analysis.

  2. Inhibition Assays:

    • Vero E6 cells were infected with SARS-CoV-2 in the presence of different concentrations of hrsACE2 to assess its inhibitory effects on viral replication, measured by qRT-PCR.
    • The efficacy of hrsACE2 was compared with murine soluble ACE2 (mrsACE2), which showed no inhibitory effect.

  3. Human Organoid Models:

    • Engineered human blood vessel and kidney organoids were developed from induced pluripotent stem cells (iPSCs) to study SARS-CoV-2 infections.
    • The organoids were infected with SARS-CoV-2, and the effects of hrsACE2 on viral replication were assessed.
Mermaid diagram

Key Results and Findings ​

  • hrsACE2 Effectiveness: hrsACE2 significantly reduced SARS-CoV-2 recovery from Vero E6 cells by 1,000–5,000 times, demonstrating a strong dose-dependent inhibition of viral entry.
  • Organoid Infections: Both blood vessel and kidney organoids were shown to be susceptible to SARS-CoV-2 infection, and treatment with hrsACE2 markedly reduced viral replication in these models.
  • Safety Profile: Neither hrsACE2 nor mrsACE2 exhibited cytotoxic effects on the Vero E6 cells or organoids during the experiments.

Main Conclusions/Significance/Innovation ​

The findings provide compelling evidence that clinical-grade hrsACE2 can effectively inhibit SARS-CoV-2 infections in vitro, highlighting its potential as a therapeutic agent for COVID-19. The study innovatively utilizes human organoid models to mimic viral infections and assess therapeutic interventions, which may offer insights into the pathogenesis of COVID-19 and the role of ACE2 in multi-organ dysfunction.

Research Limitations and Future Directions ​

  • Focus on Early Infection Stages: The study primarily addresses the early stages of infection; thus, the effects of hrsACE2 on later stages of COVID-19 remain unexplored.
  • Lung Organoids Not Studied: The absence of lung organoid studies limits understanding of hrsACE2's impact on the primary target organ in COVID-19.
  • Complexity of RAS System: The study acknowledges the complexity of the renin-angiotensin system (RAS) and suggests that further research is necessary to elucidate the full therapeutic potential of hrsACE2, particularly in vivo and across different organ systems affected by SARS-CoV-2.

Future studies should aim to explore the long-term effects of hrsACE2 treatment and its potential in clinical settings, including trials in patients with severe COVID-19.

References ​

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Literatures Citing This Work ​

  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)

... (1336 more literatures)

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