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

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Summary

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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Highlights

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Soluble human ACE2 can inhibit SARS-CoV-2 infections
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SARS-CoV-2 can directly infect human blood vessel and kidney organoids
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Human organoids as model systems to study SARS-CoV-2 infections/COVID-19

Abstract

Clinical-grade recombinant human ACE2 can reduce SARS-CoV-2 infection in cells and in multiple human organoid models.

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Most cited references 9

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice.

Timothy Sheahan, Stuart Graham, E. Anna Johnston … (2008)

Defining prospective pathways by which zoonoses evolve and emerge as human pathogens is critical for anticipating and controlling both natural and deliberate pandemics. However, predicting tenable pathways of animal-to-human movement has been hindered by challenges in identifying reservoir species, cultivating zoonotic organisms in culture, and isolating full-length genomes for cloning and genetic studies. The ability to design and recover pathogens reconstituted from synthesized cDNAs has the potential to overcome these obstacles by allowing studies of replication and pathogenesis without identification of reservoir species or cultivation of primary isolates. Here, we report the design, synthesis, and recovery of the largest synthetic replicating life form, a 29.7-kb bat severe acute respiratory syndrome (SARS)-like coronavirus (Bat-SCoV), a likely progenitor to the SARS-CoV epidemic. To test a possible route of emergence from the noncultivable Bat-SCoV to human SARS-CoV, we designed a consensus Bat-SCoV genome and replaced the Bat-SCoV Spike receptor-binding domain (RBD) with the SARS-CoV RBD (Bat-SRBD). Bat-SRBD was infectious in cell culture and in mice and was efficiently neutralized by antibodies specific for both bat and human CoV Spike proteins. Rational design, synthesis, and recovery of hypothetical recombinant viruses can be used to investigate mechanisms of transspecies movement of zoonoses and has great potential to aid in rapid public health responses to known or predicted emerging microbial threats.

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Human blood vessel organoids as a model of diabetic vasculopathy

Reiner A Wimmer, Alexandra Leopoldi, Martin Aichinger … (2019)

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Author and article information

Contributors

Nuria Montserrat

Ali Mirazimi

Josef M. Penninger

Journal

Journal ID (nlm-ta): Cell

Journal ID (iso-abbrev): Cell

Title: Cell

Publisher: Elsevier Inc.

ISSN (Print): 0092-8674

ISSN (Electronic): 1097-4172

Publication date PMC-release: 24 April 2020

Publication date (Electronic): 24 April 2020

Affiliations

[1 ]Karolinska Institute and Karolinska University Hospital, Department of Laboratory Medicine, Unit of Clinical Microbiology, 17177 Stockholm, Sweden

[2 ]National Veterinary Institute, 751 89 Uppsala, Sweden

[3 ]Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), 08028 Barcelona, Spain

[4 ]Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria

[5 ]STEMCELL Technologies, Vancouver, BC V6A 1B6, Canada

[6 ]Cell Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain

[7 ]Apeiron Biologics, Campus Vienna Biocenter 5, 1030 Vienna, Austria

[8 ]Keenan Research Centre for Biomedical Science at Li Ka Shing Knowledge Institute of St. Michael Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada

[9 ]Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain

[10 ]Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain

[11 ]Department of Medical Genetics, Life Science Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada

Author notes

[∗ ]Corresponding author nmontserrat@ 123456ibecbarcelona.eu

[∗∗ ]Corresponding author ali.mirazimi@ 123456sva.se

[∗∗∗ ]Corresponding author josef.penninger@ 123456ubc.ca

[12]

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Publisher ID: S0092-8674(20)30399-8

DOI: 10.1016/j.cell.2020.04.004

PMC ID: 7181998

PubMed ID: 32333836

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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

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Novel Coronavirus Disease COVID-19

Most cited references 9

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice.

Human blood vessel organoids as a model of diabetic vasculopathy

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