ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs

Ivan T. Lee; Tsuguhisa Nakayama; Chien Ting Wu; Yury Goltsev; Sizun Jiang; Phillip A. Gall; Chun Kang Liao; Liang Chun Shih; Christian M. Schürch; David R. McIlwain; Pauline Chu; Nicole A. Borchard; David Zarabanda; Sachi S. Dholakia; Angela Yang; Dayoung Kim; Han Chen; Tomoharu Kanie; Chia Der Lin; Ming Hsui Tsai; Katie M. Phillips; Raymond Kim; Jonathan B. Overdevest; Matthew A. Tyler; Carol H. Yan; Chih Feng Lin; Yi Tsen Lin; Da Tian Bau; Gregory J. Tsay; Zara M. Patel; Yung An Tsou; Alexandar Tzankov; Matthias S. Matter; Chih Jaan Tai; Te Huei Yeh; Peter H. Hwang; Garry P. Nolan; Jayakar V. Nayak; Peter K. Jackson

doi:10.1038/s41467-020-19145-6

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs

Ivan T. Lee, Tsuguhisa Nakayama, Chien Ting Wu, Yury Goltsev, Sizun Jiang, Phillip A. Gall, Chun Kang Liao, Liang Chun Shih, Christian M. Schürch, David R. McIlwain, Pauline Chu, Nicole A. Borchard, David Zarabanda, Sachi S. Dholakia, Angela Yang, Dayoung Kim, Han Chen, Tomoharu Kanie, Chia Der Lin, Ming Hsui TsaiKatie M. Phillips, Raymond Kim, Jonathan B. Overdevest, Matthew A. Tyler, Carol H. Yan, Chih Feng Lin, Yi Tsen Lin, Da Tian Bau, Gregory J. Tsay, Zara M. Patel, Yung An Tsou, Alexandar Tzankov, Matthias S. Matter, Chih Jaan Tai, Te Huei Yeh, Peter H. Hwang, Garry P. Nolan, Jayakar V. Nayak, Peter K. Jackson

Otolaryngology

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155 Scopus citations

Abstract

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate 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 human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Original language	English (US)
Article number	5453
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19145-6
State	Published - Dec 1 2020

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Publisher Copyright:
© 2020, The Author(s).

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Lee, I. T., Nakayama, T., Wu, C. T., Goltsev, Y., Jiang, S., Gall, P. A., Liao, C. K., Shih, L. C., Schürch, C. M., McIlwain, D. R., Chu, P., Borchard, N. A., Zarabanda, D., Dholakia, S. S., Yang, A., Kim, D., Chen, H., Kanie, T., Lin, C. D., ... Jackson, P. K. (2020). ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nature communications, 11(1), Article 5453. https://doi.org/10.1038/s41467-020-19145-6

Lee, IT, Nakayama, T, Wu, CT, Goltsev, Y, Jiang, S, Gall, PA, Liao, CK, Shih, LC, Schürch, CM, McIlwain, DR, Chu, P, Borchard, NA, Zarabanda, D, Dholakia, SS, Yang, A, Kim, D, Chen, H, Kanie, T, Lin, CD, Tsai, MH, Phillips, KM, Kim, R, Overdevest, JB, Tyler, MA, Yan, CH, Lin, CF, Lin, YT, Bau, DT, Tsay, GJ, Patel, ZM, Tsou, YA, Tzankov, A, Matter, MS, Tai, CJ, Yeh, TH, Hwang, PH, Nolan, GP, Nayak, JV & Jackson, PK 2020, 'ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs', Nature communications, vol. 11, no. 1, 5453. https://doi.org/10.1038/s41467-020-19145-6

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abstract = "The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate 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 human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.",

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AU - Nakayama, Tsuguhisa

AU - Wu, Chien Ting

AU - Goltsev, Yury

AU - Jiang, Sizun

AU - Gall, Phillip A.

AU - Liao, Chun Kang

AU - Shih, Liang Chun

AU - Schürch, Christian M.

AU - McIlwain, David R.

AU - Chu, Pauline

AU - Borchard, Nicole A.

AU - Zarabanda, David

AU - Dholakia, Sachi S.

AU - Yang, Angela

AU - Kim, Dayoung

AU - Chen, Han

AU - Kanie, Tomoharu

AU - Lin, Chia Der

AU - Tsai, Ming Hsui

AU - Phillips, Katie M.

AU - Kim, Raymond

AU - Overdevest, Jonathan B.

AU - Tyler, Matthew A.

AU - Yan, Carol H.

AU - Lin, Chih Feng

AU - Lin, Yi Tsen

AU - Bau, Da Tian

AU - Tsay, Gregory J.

AU - Patel, Zara M.

AU - Tsou, Yung An

AU - Tzankov, Alexandar

AU - Matter, Matthias S.

AU - Tai, Chih Jaan

AU - Yeh, Te Huei

AU - Hwang, Peter H.

AU - Nolan, Garry P.

AU - Nayak, Jayakar V.

AU - Jackson, Peter K.

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ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs

Abstract

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