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 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

Otolaryngology

Research output: Contribution to journal › Article › peer-review

198 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 - Oct 28 2020

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Age Factors
Angiotensin Receptor Antagonists/therapeutic use
Angiotensin-Converting Enzyme 2
Angiotensin-Converting Enzyme Inhibitors/therapeutic use
COVID-19
Cilia/metabolism
Coronavirus Infections/pathology
Endothelial Cells
Gene Expression/drug effects
Goblet Cells/metabolism
Humans
Lung/pathology
Pandemics
Peptidyl-Dipeptidase A/genetics
Pneumonia, Viral/pathology
Respiratory System/metabolism
Sex Factors
Sinusitis/metabolism
Smoking

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Journal Article
Research Support, N.I.H., Extramural

Publisher link

10.1038/s41467-020-19145-6

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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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title = "ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs",

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

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = oct,

day = "28",

doi = "10.1038/s41467-020-19145-6",

language = "English (US)",

volume = "11",

journal = "Nature communications",

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T1 - ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs

AU - Lee, Ivan T.

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.

PY - 2020/10/28

Y1 - 2020/10/28

N2 - 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.

AB - 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.

KW - Age Factors

KW - Angiotensin Receptor Antagonists/therapeutic use

KW - Angiotensin-Converting Enzyme 2

KW - Angiotensin-Converting Enzyme Inhibitors/therapeutic use

KW - COVID-19

KW - Cilia/metabolism

KW - Coronavirus Infections/pathology

KW - Endothelial Cells

KW - Gene Expression/drug effects

KW - Goblet Cells/metabolism

KW - Humans

KW - Lung/pathology

KW - Pandemics

KW - Peptidyl-Dipeptidase A/genetics

KW - Pneumonia, Viral/pathology

KW - Respiratory System/metabolism

KW - Sex Factors

KW - Sinusitis/metabolism

KW - Smoking

UR - https://www.scopus.com/pages/publications/85094215416

UR - https://www.scopus.com/pages/publications/85094215416#tab=citedBy

U2 - 10.1038/s41467-020-19145-6

DO - 10.1038/s41467-020-19145-6

M3 - Article

C2 - 33116139

AN - SCOPUS:85094215416

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5453

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

PubMed: MeSH publication types

Publisher link

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