Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers

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Abstract

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

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Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

Dawei Wang, Bo Hu, Fangfang Zhu … (2020)

In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Journal

Journal ID (nlm-ta): medRxiv

Journal ID (publisher-id): MEDRXIV

Title: medRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 12 May 2020

Electronic Location Identifier: 2020.05.08.20092866

Affiliations

[1 ]Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA

[2 ]Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, 801 Welch Road, Stanford, CA, USA

[3 ]Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

[4 ]Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA

[5 ]Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan

[6 ]Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan

[7 ]Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

[8 ]Terry Fox Cancer Research Laboratory, Translational Medicine Center, China Medical University Hospital, Taichung, Taiwan

[9 ]School of Medicine, China Medical University, Taichung, Taiwan

[10 ]Department of Otolaryngology–Head and Neck Surgery, Columbia University School of Medicine, New York City, NY.

[11 ]Department of Otolaryngology–Head and Neck Surgery, University of Minnesota School of Medicine, Minneapolis, MN.

[12 ]Department of Otolaryngology–Head and Neck Surgery, University of California San Diego School of Medicine, San Diego, CA.

[13 ]Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.

[14 ]These authors contributed equally: Ivan T. Lee, Tsuguhisa Nakayama, Chien-Ting Wu, Yury Goltsev

[15 ]These authors jointly supervised this work: Garry P. Nolan, Jayakar V. Nayak, Peter K. Jackson.

Author notes

Author Contributions

I.T.L. conceived and coordinated the study. I.T.L., T.N., C-T.W., S.J., P.A.G. designed and performed the experiments. C-T.W. performed the microscopy imaging. I.T.L., T.N., P.A.G., C-K.L., L-C.S., C.M.S., D.R.M., P.C., N.A.B., D.Z, S.S.D., A.Y., D.K., K.M.P., R.K., J.B.O., M.A.T., C.H.Y., Y-T.L, C-F. L., D-T.B., G.J.T., Z.M.P., Y-A.T., C-J.T., T-H.Y., P.H.H. consented patients, collected, processed, banked, and/or evaluated the human samples. I.T.L., T.N., C-T.W., Y.G., S.J. analyzed the data. Y.G. developed and performed computational image processing. Y.G. and T.N. conducted statistical analyses. T.N. and C-T.W. prepared the final figures. I.T.L. wrote the manuscript with contributions by T.N., C-T.W., Y.G., S.J., C.M.S., D.R.M., P.C., G.P.N., J.V.N., P.K.J. Funding and supervision were provided by G.P.N., J.V.N., and P.K.J.

[16 ]Corresponding author: Garry P. Nolan ( gnolan@ 123456stanford.edu )

Article

DOI: 10.1101/2020.05.08.20092866

PMC ID: 7273284

PubMed ID: 32511516

SO-VID: e30ed4b5-9fb6-4fb5-b851-e4cf8f23c526

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This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.

Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers

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Novel Coronavirus Disease COVID-19

Most cited references 36

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

A pneumonia outbreak associated with a new coronavirus of probable bat origin

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

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