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
Nature Communications, doi:10.1038/s41467-020-19145-6
ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs Ivan T
G., and S.J., contributed equally and have the right to list their name first in their CV. Funding and supervision were provided by G.P.N., J.V.N., and P.K.J. All authors reviewed and agreed with the content of this manuscript.
Competing interests The authors declare no competing interests.
References
Antunes, Cohen, Rhinology and Facial Plastic Surgery
Bertram, Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts, PLoS ONE
Davies, Age-dependent effects in the transmission and control of COVID-19 epidemics, Nat. Med
De Abajo, Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study, Lancet
Diaz, Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19, J. Travel Med
Esler, Esler, Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?, J. Hypertens
Fang, Karakiulakis, Roth, Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?, Lancet Respir. Med
Ferrario, Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2, Circulation
Fosbøl, Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality, JAMA
Furuhashi, Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker, Am. J. Hypertens
Grasselli, Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy, JAMA
Guo, Huang, Lin, Lv, Coronavirus Disease 2019 (COVID-19) and cardiovascular disease: a viewpoint on the potential influence of angiotensinconverting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection, J. Am. Heart Assoc
Hamming, Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis, J. Pathol
Harmer, Gilbert, Borman, Clark, Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme, FEBS Lett
Hikmet, Méar, Uhlén, Lindskog, The protein expression profile of ACE2 in human tissues, Mol. Syst. Biol
Hoffmann, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Hofmann, Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor, Biochem. Biophys. Res. Commun
Hui, Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures, Lancet Respir. Med
Jeong, CX3CR1 is expressed in differentiated human ciliated airway cells and co-localizes with respiratory syncytial virus on cilia in a G proteindependent manner, PLoS ONE
Lee, Nakayama, Wu, Goltsev, Jiang, None
Lee, None, Tsuguhisa Nakayama
Leopold, Smoking is associated with shortened airway cilia, PLoS ONE
Li, The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2, Virology
Limburg, TMPRSS2 is the major activating protease of influenza a virus in primary human airway cells and influenza b virus in human type II pneumocytes, J. Virol
Mancia, Rea, Ludergnani, Apolone, Corrao, Renin-angiotensin-aldosterone system blockers and the risk of Covid-19, N. Engl. J. Med
Menter, Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction, Histopathology
Muus, Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells,
doi:10.1101/2020.04.19.049254Ortiz, Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract, EBioMedicine
Pai, Muo, Sung, Ho, Lee, Angiotensin receptor blockers (ARB) outperform angiotensin-converting enzyme (ACE) inhibitors on ischemic stroke prevention in patients with hypertension and diabetes -A real-world population study in Taiwan, Int. J. Cardiol
Patanavanich, Glantz, Smoking is associated with COVID-19 progression: a meta-analysis, Nicotine Tob. Res
Patel, Zhong, Grant, Oudit, Role of the ACE2/ Angiotensin 1-7 axis of the renin-angiotensin system in heart failure, Circ. Res
Phillip, Gall, Liao 6, Shih 7 ; Christian, Schürch et al., None, Peter K. Jackson
Qi, Qian, Zhang, Zhang, Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses, Biochem. Biophys. Res. Commun
Reho, Guo, Morgan, Rahmouni, Smooth muscle cell-specific disruption of the BBSome causes vascular dysfunction, Hypertension
Reynolds, Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19, N. Engl. J. Med
Rockx, Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model, Science
Sims, Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs, J. Virol
Smith, Sheltzer, Cigarette smoke triggers the expansion of a subpopulation of respiratory epithelial cells that express the SARS-CoV-2 receptor ACE2,
doi:10.1101/2020.03.28.013672Soler, Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan, Am. J. Physiol. Renal. Physiol
Sommerstein, Gräni, Preventing a COVID-19 pandemic: ACE inhibitors as a potential risk factor for fatal COVID-19, BMJ
Sungnak, SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes, Nat. Med
Tan, In vitro model of fully differentiated human nasal epithelial cells infected with rhinovirus reveals epithelium-initiated immune responses, J. Infect. Dis
Team, Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -United States, February 12-March 28, 2020, MMWR Morb. Mortal. Wkly Rep
Thompson, Barclay, Zambon, Pickles, Infection of human airway epithelium by human and avian strains of influenza a virus, J. Virol
Wang, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA
Widagdo, Species-specific colocalization of middle east respiratory syndrome coronavirus attachment and entry receptors, J. Virol
Wu, A new coronavirus associated with human respiratory disease in China, Nature
Xie, Tong, Guan, Du, Qiu, Clinical characteristics of patients who died of coronavirus disease 2019 in China, JAMA Netw. Open
Zhang, Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium, J. Virol
Zhang, Peeples, Boucher, Collins, Pickles, Respiratory syncytial virus infection of human airway epithelial cells is polarized, specific to ciliated cells, and without obvious cytopathology, J. Virol
Zhou, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature
Ziegler, SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues, Cell
{ 'indexed': {'date-parts': [[2024, 6, 17]], 'date-time': '2024-06-17T19:14:08Z', 'timestamp': 1718651648234},
'reference-count': 49,
'publisher': 'Springer Science and Business Media LLC',
'issue': '1',
'license': [ { 'start': { 'date-parts': [[2020, 10, 28]],
'date-time': '2020-10-28T00:00:00Z',
'timestamp': 1603843200000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'},
{ 'start': { 'date-parts': [[2020, 10, 28]],
'date-time': '2020-10-28T00:00:00Z',
'timestamp': 1603843200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'abstract': '<jats:title>Abstract</jats:title><jats:p>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.</jats:p>',
'DOI': '10.1038/s41467-020-19145-6',
'type': 'journal-article',
'created': { 'date-parts': [[2020, 10, 28]],
'date-time': '2020-10-28T11:24:39Z',
'timestamp': 1603884279000},
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 177,
'title': 'ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs',
'prefix': '10.1038',
'volume': '11',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-5446-2046',
'authenticated-orcid': False,
'given': 'Ivan T.',
'family': 'Lee',
'sequence': 'first',
'affiliation': []},
{'given': 'Tsuguhisa', 'family': 'Nakayama', 'sequence': 'additional', 'affiliation': []},
{'given': 'Chien-Ting', 'family': 'Wu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yury', 'family': 'Goltsev', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6149-3142',
'authenticated-orcid': False,
'given': 'Sizun',
'family': 'Jiang',
'sequence': 'additional',
'affiliation': []},
{'given': 'Phillip A.', 'family': 'Gall', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-0037-1421',
'authenticated-orcid': False,
'given': 'Chun-Kang',
'family': 'Liao',
'sequence': 'additional',
'affiliation': []},
{'given': 'Liang-Chun', 'family': 'Shih', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1792-1768',
'authenticated-orcid': False,
'given': 'Christian M.',
'family': 'Schürch',
'sequence': 'additional',
'affiliation': []},
{'given': 'David R.', 'family': 'McIlwain', 'sequence': 'additional', 'affiliation': []},
{'given': 'Pauline', 'family': 'Chu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Nicole A.', 'family': 'Borchard', 'sequence': 'additional', 'affiliation': []},
{'given': 'David', 'family': 'Zarabanda', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sachi S.', 'family': 'Dholakia', 'sequence': 'additional', 'affiliation': []},
{'given': 'Angela', 'family': 'Yang', 'sequence': 'additional', 'affiliation': []},
{'given': 'Dayoung', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1722-8736',
'authenticated-orcid': False,
'given': 'Han',
'family': 'Chen',
'sequence': 'additional',
'affiliation': []},
{'given': 'Tomoharu', 'family': 'Kanie', 'sequence': 'additional', 'affiliation': []},
{'given': 'Chia-Der', 'family': 'Lin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ming-Hsui', 'family': 'Tsai', 'sequence': 'additional', 'affiliation': []},
{'given': 'Katie M.', 'family': 'Phillips', 'sequence': 'additional', 'affiliation': []},
{'given': 'Raymond', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1152-2512',
'authenticated-orcid': False,
'given': 'Jonathan B.',
'family': 'Overdevest',
'sequence': 'additional',
'affiliation': []},
{'given': 'Matthew A.', 'family': 'Tyler', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-1934-4922',
'authenticated-orcid': False,
'given': 'Carol H.',
'family': 'Yan',
'sequence': 'additional',
'affiliation': []},
{'given': 'Chih-Feng', 'family': 'Lin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yi-Tsen', 'family': 'Lin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Da-Tian', 'family': 'Bau', 'sequence': 'additional', 'affiliation': []},
{'given': 'Gregory J.', 'family': 'Tsay', 'sequence': 'additional', 'affiliation': []},
{'given': 'Zara M.', 'family': 'Patel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yung-An', 'family': 'Tsou', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1100-3819',
'authenticated-orcid': False,
'given': 'Alexandar',
'family': 'Tzankov',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-2005-5266',
'authenticated-orcid': False,
'given': 'Matthias S.',
'family': 'Matter',
'sequence': 'additional',
'affiliation': []},
{'given': 'Chih-Jaan', 'family': 'Tai', 'sequence': 'additional', 'affiliation': []},
{'given': 'Te-Huei', 'family': 'Yeh', 'sequence': 'additional', 'affiliation': []},
{'given': 'Peter H.', 'family': 'Hwang', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-8862-9043',
'authenticated-orcid': False,
'given': 'Garry P.',
'family': 'Nolan',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-4454-0861',
'authenticated-orcid': False,
'given': 'Jayakar V.',
'family': 'Nayak',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-1742-2539',
'authenticated-orcid': False,
'given': 'Peter K.',
'family': 'Jackson',
'sequence': 'additional',
'affiliation': []}],
'member': '297',
'published-online': {'date-parts': [[2020, 10, 28]]},
'reference': [ { 'key': '19145_CR1',
'doi-asserted-by': 'crossref',
'first-page': '265',
'DOI': '10.1038/s41586-020-2008-3',
'volume': '579',
'author': 'F Wu',
'year': '2020',
'unstructured': 'Wu, F. et al. A new coronavirus associated with human respiratory '
'disease in China. Nature 579, 265–269 (2020).',
'journal-title': 'Nature'},
{ 'key': '19145_CR2',
'doi-asserted-by': 'publisher',
'first-page': '1061',
'DOI': '10.1001/jama.2020.1585',
'volume': '323',
'author': 'D Wang',
'year': '2020',
'unstructured': 'Wang, D. et al. Clinical characteristics of 138 hospitalized patients '
'with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA '
'323, 1061–1069 (2020).',
'journal-title': 'JAMA'},
{ 'key': '19145_CR3',
'doi-asserted-by': 'crossref',
'unstructured': 'Grasselli, G. et al. Baseline characteristics and outcomes of 1591 '
'patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy '
'Region, Italy. JAMA 323, 1574–1581 (2020).',
'DOI': '10.1001/jama.2020.5394'},
{ 'key': '19145_CR4',
'doi-asserted-by': 'publisher',
'first-page': 'e205619',
'DOI': '10.1001/jamanetworkopen.2020.5619',
'volume': '3',
'author': 'J Xie',
'year': '2020',
'unstructured': 'Xie, J., Tong, Z., Guan, X., Du, B. & Qiu, H. Clinical characteristics '
'of patients who died of coronavirus disease 2019 in China. JAMA Netw. '
'Open 3, e205619 (2020).',
'journal-title': 'JAMA Netw. Open'},
{ 'key': '19145_CR5',
'doi-asserted-by': 'publisher',
'first-page': '382',
'DOI': '10.15585/mmwr.mm6913e2',
'volume': '69',
'author': 'CDC COVID-19 Response Team.',
'year': '2020',
'unstructured': 'CDC COVID-19 Response Team. et al. Preliminary estimates of the '
'prevalence of selected underlying health conditions among patients with '
'coronavirus disease 2019 - United States, February 12-March 28, 2020. '
'MMWR Morb. Mortal. Wkly Rep. 69, 382–386 (2020).',
'journal-title': 'MMWR Morb. Mortal. Wkly Rep.'},
{ 'key': '19145_CR6',
'doi-asserted-by': 'publisher',
'first-page': '270',
'DOI': '10.1038/s41586-020-2012-7',
'volume': '579',
'author': 'P Zhou',
'year': '2020',
'unstructured': 'Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus '
'of probable bat origin. Nature 579, 270–273 (2020).',
'journal-title': 'Nature'},
{ 'key': '19145_CR7',
'doi-asserted-by': 'publisher',
'first-page': '271',
'DOI': '10.1016/j.cell.2020.02.052',
'volume': '181',
'author': 'M Hoffmann',
'year': '2020',
'unstructured': 'Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 '
'and is blocked by a clinically proven protease inhibitor. Cell 181, '
'271–280.e8 (2020).',
'journal-title': 'Cell'},
{ 'key': '19145_CR8',
'doi-asserted-by': 'publisher',
'first-page': '1313',
'DOI': '10.1161/CIRCRESAHA.116.307708',
'volume': '118',
'author': 'VB Patel',
'year': '2016',
'unstructured': 'Patel, V. B., Zhong, J.-C., Grant, M. B. & Oudit, G. Y. Role of the '
'ACE2/Angiotensin 1-7 axis of the renin-angiotensin system in heart '
'failure. Circ. Res. 118, 1313–1326 (2016).',
'journal-title': 'Circ. Res.'},
{ 'key': '19145_CR9',
'doi-asserted-by': 'publisher',
'first-page': 'e21',
'DOI': '10.1016/S2213-2600(20)30116-8',
'volume': '8',
'author': 'L Fang',
'year': '2020',
'unstructured': 'Fang, L., Karakiulakis, G. & Roth, M. Are patients with hypertension and '
'diabetes mellitus at increased risk for COVID-19 infection?\xa0Lancet '
'Respir. Med. 8, e21 (2020).',
'journal-title': 'Lancet Respir. Med.'},
{ 'key': '19145_CR10',
'doi-asserted-by': 'crossref',
'unstructured': 'Esler, M. & Esler, D. Can angiotensin receptor-blocking drugs perhaps be '
'harmful in the COVID-19 pandemic? J. Hypertens. 38, 1 (2020).',
'DOI': '10.1097/HJH.0000000000002450'},
{ 'key': '19145_CR11',
'doi-asserted-by': 'publisher',
'first-page': 'taaa041',
'DOI': '10.1093/jtm/taaa041',
'volume': '27',
'author': 'JH Diaz',
'year': '2020',
'unstructured': 'Diaz, J. H. Hypothesis: angiotensin-converting enzyme inhibitors and '
'angiotensin receptor blockers may increase the risk of severe COVID-19. '
'J. Travel Med. 27, taaa041 (2020).',
'journal-title': 'J. Travel Med.'},
{ 'key': '19145_CR12',
'first-page': 'm810',
'volume': '368',
'author': 'R Sommerstein',
'year': '2020',
'unstructured': 'Sommerstein, R. & Gräni, C. Preventing a COVID-19 pandemic: ACE '
'inhibitors as a potential risk factor for fatal COVID-19. BMJ 368, m810 '
'(2020).',
'journal-title': 'BMJ'},
{ 'key': '19145_CR13',
'doi-asserted-by': 'publisher',
'first-page': '2605',
'DOI': '10.1161/CIRCULATIONAHA.104.510461',
'volume': '111',
'author': 'CM Ferrario',
'year': '2005',
'unstructured': 'Ferrario, C. M. et al. Effect of angiotensin-converting enzyme '
'inhibition and angiotensin II receptor blockers on cardiac '
'angiotensin-converting enzyme 2. Circulation 111, 2605–2610 (2005).',
'journal-title': 'Circulation'},
{ 'key': '19145_CR14',
'doi-asserted-by': 'publisher',
'first-page': 'F398',
'DOI': '10.1152/ajprenal.90488.2008',
'volume': '296',
'author': 'MJ Soler',
'year': '2009',
'unstructured': 'Soler, M. J. et al. Localization of ACE2 in the renal vasculature: '
'amplification by angiotensin II type 1 receptor blockade using '
'telmisartan. Am. J. Physiol. Renal. Physiol. 296, F398–F405 (2009).',
'journal-title': 'Am. J. Physiol. Renal. Physiol.'},
{ 'key': '19145_CR15',
'doi-asserted-by': 'publisher',
'first-page': '15',
'DOI': '10.1093/ajh/hpu086',
'volume': '28',
'author': 'M Furuhashi',
'year': '2015',
'unstructured': 'Furuhashi, M. et al. Urinary angiotensin-converting enzyme 2 in '
'hypertensive patients may be increased by olmesartan, an angiotensin II '
'receptor blocker. Am. J. Hypertens. 28, 15–21 (2015).',
'journal-title': 'Am. J. Hypertens.'},
{ 'key': '19145_CR16',
'doi-asserted-by': 'publisher',
'first-page': '107',
'DOI': '10.1016/S0014-5793(02)03640-2',
'volume': '532',
'author': 'D Harmer',
'year': '2002',
'unstructured': 'Harmer, D., Gilbert, M., Borman, R. & Clark, K. L. Quantitative mRNA '
'expression profiling of ACE 2, a novel homologue of angiotensin '
'converting enzyme. FEBS Lett. 532, 107–110 (2002).',
'journal-title': 'FEBS Lett.'},
{ 'key': '19145_CR17',
'doi-asserted-by': 'publisher',
'first-page': '631',
'DOI': '10.1002/path.1570',
'volume': '203',
'author': 'I Hamming',
'year': '2004',
'unstructured': 'Hamming, I. et al. Tissue distribution of ACE2 protein, the functional '
'receptor for SARS coronavirus. A first step in understanding SARS '
'pathogenesis. J. Pathol. 203, 631–637 (2004).',
'journal-title': 'J. Pathol.'},
{ 'key': '19145_CR18',
'doi-asserted-by': 'publisher',
'first-page': 'e35876',
'DOI': '10.1371/journal.pone.0035876',
'volume': '7',
'author': 'S Bertram',
'year': '2012',
'unstructured': 'Bertram, S. et al. Influenza and SARS-coronavirus activating proteases '
'TMPRSS2 and HAT are expressed at multiple sites in human respiratory and '
'gastrointestinal tracts. PLoS ONE 7, e35876 (2012).',
'journal-title': 'PLoS ONE'},
{ 'key': '19145_CR19',
'doi-asserted-by': 'publisher',
'first-page': 'e9610',
'DOI': '10.15252/msb.20209610',
'volume': '16',
'author': 'F Hikmet',
'year': '2020',
'unstructured': 'Hikmet, F., Méar, L., Uhlén, M. & Lindskog, C. The protein expression '
'profile of ACE2 in human tissues. Mol. Syst. Biol.\xa016, e9610 (2020).',
'journal-title': 'Mol. Syst. Biol.'},
{ 'key': '19145_CR20',
'doi-asserted-by': 'publisher',
'first-page': '1016',
'DOI': '10.1016/j.cell.2020.04.035',
'volume': '181',
'author': 'C Ziegler',
'year': '2020',
'unstructured': 'Ziegler, C. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated '
'gene in human airway epithelial cells and is enriched in specific cell '
'subsets across tissues.\xa0Cell 181, 1016–1035.e19 (2020).',
'journal-title': 'Cell'},
{ 'key': '19145_CR21',
'doi-asserted-by': 'publisher',
'first-page': '681',
'DOI': '10.1038/s41591-020-0868-6',
'volume': '26',
'author': 'W Sungnak',
'year': '2020',
'unstructured': 'Sungnak, W. et al. SARS-CoV-2 entry factors are highly expressed in '
'nasal epithelial cells together with innate immune genes. Nat. Med. 26, '
'681–687 (2020).',
'journal-title': 'Nat. Med.'},
{ 'key': '19145_CR22',
'doi-asserted-by': 'publisher',
'first-page': '135',
'DOI': '10.1016/j.bbrc.2020.03.044',
'volume': '526',
'author': 'F Qi',
'year': '2020',
'unstructured': 'Qi, F., Qian, S., Zhang, S. & Zhang, Z. Single cell RNA sequencing of 13 '
'human tissues identify cell types and receptors of human '
'coronaviruses.\xa0Biochem. Biophys. Res. Commun. 526, 135–140 (2020).',
'journal-title': 'Biochem. Biophys. Res. Commun.'},
{ 'key': '19145_CR23',
'doi-asserted-by': 'crossref',
'unstructured': 'Limburg, H. et al. TMPRSS2 is the major activating protease of influenza '
'a virus in primary human airway cells and influenza b virus in human '
'type II pneumocytes. J. Virol. 93, e00649-19 (2019).',
'DOI': '10.1128/JVI.00649-19'},
{ 'key': '19145_CR24',
'doi-asserted-by': 'crossref',
'unstructured': 'Guo, J., Huang, Z., Lin, L. & Lv, J. Coronavirus Disease 2019 (COVID‐19) '
'and cardiovascular disease: a viewpoint on the potential influence of '
'angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers '
'on onset and severity of severe acute respiratory syndrome coronavirus 2 '
'infection. J. Am. Heart Assoc. 9, e016219 (2020).',
'DOI': '10.1161/JAHA.120.016219'},
{ 'key': '19145_CR25',
'doi-asserted-by': 'publisher',
'first-page': '367',
'DOI': '10.1016/j.virol.2007.04.035',
'volume': '367',
'author': 'W Li',
'year': '2007',
'unstructured': 'Li, W. et al. The S proteins of human coronavirus NL63 and severe acute '
'respiratory syndrome coronavirus bind overlapping regions of ACE2. '
'Virology 367, 367–374 (2007).',
'journal-title': 'Virology'},
{ 'key': '19145_CR26',
'doi-asserted-by': 'publisher',
'first-page': '1216',
'DOI': '10.1016/j.bbrc.2004.05.114',
'volume': '319',
'author': 'H Hofmann',
'year': '2004',
'unstructured': 'Hofmann, H. et al. Susceptibility to SARS coronavirus S protein-driven '
'infection correlates with expression of angiotensin converting enzyme 2 '
'and infection can be blocked by soluble receptor. Biochem. Biophys. Res. '
'Commun. 319, 1216–1221 (2004).',
'journal-title': 'Biochem. Biophys. Res. Commun.'},
{ 'key': '19145_CR27',
'doi-asserted-by': 'publisher',
'first-page': '1653',
'DOI': '10.1093/ntr/ntaa082',
'volume': '22',
'author': 'R Patanavanich',
'year': '2020',
'unstructured': 'Patanavanich, R. & Glantz, S. A. Smoking is associated with COVID-19 '
'progression: a meta-analysis. Nicotine Tob. Res. 22, 1653–1656 (2020).',
'journal-title': 'Nicotine Tob. Res.'},
{ 'key': '19145_CR28',
'doi-asserted-by': 'publisher',
'first-page': '1205',
'DOI': '10.1038/s41591-020-0962-9',
'volume': '26',
'author': 'NG Davies',
'year': '2020',
'unstructured': 'Davies, N. G. et al. Age-dependent effects in the transmission and '
'control of COVID-19 epidemics. Nat. Med. 26, 1205–1211 (2020).',
'journal-title': 'Nat. Med.'},
{ 'key': '19145_CR29',
'doi-asserted-by': 'publisher',
'unstructured': 'Muus, C. et al. Integrated analyses of single-cell atlases reveal age, '
'gender, and smoking status associations with cell type-specific '
'expression of mediators of SARS-CoV-2 viral entry and highlights '
'inflammatory programs in putative target cells. Preprint at\xa0bioRxiv '
'https://doi.org/10.1101/2020.04.19.049254 (2020).',
'DOI': '10.1101/2020.04.19.049254'},
{ 'key': '19145_CR30',
'doi-asserted-by': 'publisher',
'unstructured': 'Smith, J. C. & Sheltzer, J. M. Cigarette smoke triggers the expansion of '
'a subpopulation of respiratory epithelial cells that express the '
'SARS-CoV-2 receptor ACE2. Preprint at\xa0bioRxiv '
'https://doi.org/10.1101/2020.03.28.013672 (2020).',
'DOI': '10.1101/2020.03.28.013672'},
{ 'key': '19145_CR31',
'doi-asserted-by': 'publisher',
'first-page': '102976',
'DOI': '10.1016/j.ebiom.2020.102976',
'volume': '60',
'author': 'ME Ortiz',
'year': '2020',
'unstructured': 'Ortiz, M. E. et al. Heterogeneous expression of the SARS-Coronavirus-2 '
'receptor ACE2 in the human respiratory tract. EBioMedicine 60, 102976 '
'(2020).',
'journal-title': 'EBioMedicine'},
{ 'key': '19145_CR32',
'doi-asserted-by': 'publisher',
'first-page': '114',
'DOI': '10.1016/j.ijcard.2016.04.096',
'volume': '215',
'author': 'P-Y Pai',
'year': '2016',
'unstructured': 'Pai, P.-Y., Muo, C.-H., Sung, F.-C., Ho, H.-C. & Lee, Y.-T. Angiotensin '
'receptor blockers (ARB) outperform angiotensin-converting enzyme (ACE) '
'inhibitors on ischemic stroke prevention in patients with hypertension '
'and diabetes - A real-world population study in Taiwan. Int. J. Cardiol. '
'215, 114–119 (2016).',
'journal-title': 'Int. J. Cardiol.'},
{ 'key': '19145_CR33',
'doi-asserted-by': 'crossref',
'unstructured': 'Antunes, M. B. & Cohen, N. A. in Rhinology and Facial Plastic Surgery '
'(eds Stucker, F. J. et al.) 83–90 (Springer, 2009).',
'DOI': '10.1007/978-3-540-74380-4_6'},
{ 'key': '19145_CR34',
'doi-asserted-by': 'publisher',
'first-page': '817',
'DOI': '10.1161/HYPERTENSIONAHA.119.13382',
'volume': '74',
'author': 'JJ Reho',
'year': '2019',
'unstructured': 'Reho, J. J., Guo, D.-F., Morgan, D. A. & Rahmouni, K. Smooth muscle '
'cell–specific disruption of the BBSome causes vascular dysfunction. '
'Hypertension 74, 817–825 (2019).',
'journal-title': 'Hypertension'},
{ 'key': '19145_CR35',
'doi-asserted-by': 'publisher',
'first-page': '15511',
'DOI': '10.1128/JVI.79.24.15511-15524.2005',
'volume': '79',
'author': 'AC Sims',
'year': '2005',
'unstructured': 'Sims, A. C. et al. Severe acute respiratory syndrome coronavirus '
'infection of human ciliated airway epithelia: role of ciliated cells in '
'viral spread in the conducting airways of the lungs. J. Virol. 79, '
'15511–15524 (2005).',
'journal-title': 'J. Virol.'},
{ 'key': '19145_CR36',
'doi-asserted-by': 'crossref',
'unstructured': 'Widagdo, W. et al. Species-specific colocalization of middle east '
'respiratory syndrome coronavirus attachment and entry receptors. J. '
'Virol. 93, e00107-19 (2019).',
'DOI': '10.1128/JVI.00107-19'},
{ 'key': '19145_CR37',
'doi-asserted-by': 'publisher',
'first-page': '5654',
'DOI': '10.1128/JVI.76.11.5654-5666.2002',
'volume': '76',
'author': 'L Zhang',
'year': '2002',
'unstructured': 'Zhang, L., Peeples, M. E., Boucher, R. C., Collins, P. L. & Pickles, R. '
'J. Respiratory syncytial virus infection of human airway epithelial '
'cells is polarized, specific to ciliated cells, and without obvious '
'cytopathology. J. Virol. 76, 5654–5666 (2002).',
'journal-title': 'J. Virol.'},
{ 'key': '19145_CR38',
'doi-asserted-by': 'publisher',
'first-page': '8060',
'DOI': '10.1128/JVI.00384-06',
'volume': '80',
'author': 'CI Thompson',
'year': '2006',
'unstructured': 'Thompson, C. I., Barclay, W. S., Zambon, M. C. & Pickles, R. J. '
'Infection of human airway epithelium by human and avian strains of '
'influenza a virus. J. Virol. 80, 8060–8068 (2006).',
'journal-title': 'J. Virol.'},
{ 'key': '19145_CR39',
'doi-asserted-by': 'publisher',
'first-page': '906',
'DOI': '10.1093/infdis/jix640',
'volume': '217',
'author': 'KS Tan',
'year': '2018',
'unstructured': 'Tan, K. S. et al. In vitro model of fully differentiated human nasal '
'epithelial cells infected with rhinovirus reveals epithelium-initiated '
'immune responses. J. Infect. Dis. 217, 906–915 (2018).',
'journal-title': 'J. Infect. Dis.'},
{ 'key': '19145_CR40',
'doi-asserted-by': 'publisher',
'first-page': '1113',
'DOI': '10.1128/JVI.79.2.1113-1124.2005',
'volume': '79',
'author': 'L Zhang',
'year': '2005',
'unstructured': 'Zhang, L. et al. Infection of ciliated cells by human parainfluenza '
'virus type 3 in an in vitro model of human airway epithelium. J. Virol. '
'79, 1113–1124 (2005).',
'journal-title': 'J. Virol.'},
{ 'key': '19145_CR41',
'doi-asserted-by': 'publisher',
'first-page': 'e0130517',
'DOI': '10.1371/journal.pone.0130517',
'volume': '10',
'author': 'K-I Jeong',
'year': '2015',
'unstructured': 'Jeong, K.-I. et al. CX3CR1 is expressed in differentiated human ciliated '
'airway cells and co-localizes with respiratory syncytial virus on cilia '
'in a G protein-dependent manner. PLoS ONE 10, e0130517 (2015).',
'journal-title': 'PLoS ONE'},
{ 'key': '19145_CR42',
'doi-asserted-by': 'publisher',
'first-page': '1012',
'DOI': '10.1126/science.abb7314',
'volume': '368',
'author': 'B Rockx',
'year': '2020',
'unstructured': 'Rockx, B. et al. Comparative pathogenesis of COVID-19, MERS, and SARS in '
'a nonhuman primate model. Science 368, 1012–1015 (2020).',
'journal-title': 'Science'},
{ 'key': '19145_CR43',
'doi-asserted-by': 'publisher',
'first-page': '687',
'DOI': '10.1016/S2213-2600(20)30193-4',
'volume': '8',
'author': 'KPY Hui',
'year': '2020',
'unstructured': 'Hui, K. P. Y. et al. Tropism, replication competence, and innate immune '
'responses of the coronavirus SARS-CoV-2 in human respiratory tract and '
'conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet '
'Respir. Med. 8, 687–695 (2020).',
'journal-title': 'Lancet Respir. Med.'},
{ 'key': '19145_CR44',
'doi-asserted-by': 'publisher',
'first-page': 'e8157',
'DOI': '10.1371/journal.pone.0008157',
'volume': '4',
'author': 'PL Leopold',
'year': '2009',
'unstructured': 'Leopold, P. L. et al. Smoking is associated with shortened airway cilia. '
'PLoS ONE 4, e8157 (2009).',
'journal-title': 'PLoS ONE'},
{ 'key': '19145_CR45',
'doi-asserted-by': 'publisher',
'first-page': '2441',
'DOI': '10.1056/NEJMoa2008975',
'volume': '382',
'author': 'HR Reynolds',
'year': '2020',
'unstructured': 'Reynolds, H. R. et al. Renin–angiotensin–aldosterone system inhibitors '
'and risk of Covid-19. N. Engl. J. Med. 382, 2441–2448 (2020).',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': '19145_CR46',
'doi-asserted-by': 'publisher',
'first-page': '2431',
'DOI': '10.1056/NEJMoa2006923',
'volume': '382',
'author': 'G Mancia',
'year': '2020',
'unstructured': 'Mancia, G., Rea, F., Ludergnani, M., Apolone, G. & Corrao, G. '
'Renin–angiotensin–aldosterone system blockers and the risk of Covid-19. '
'N. Engl. J. Med. 382, 2431–2440 (2020).',
'journal-title': 'N. Engl. J. Med.'},
{ 'key': '19145_CR47',
'doi-asserted-by': 'publisher',
'first-page': '168',
'DOI': '10.1001/jama.2020.11301',
'volume': '324',
'author': 'EL Fosbøl',
'year': '2020',
'unstructured': 'Fosbøl, E. L. et al. Association of angiotensin-converting enzyme '
'inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis '
'and mortality. JAMA 324, 168–177 (2020).',
'journal-title': 'JAMA'},
{ 'key': '19145_CR48',
'doi-asserted-by': 'publisher',
'first-page': '1705',
'DOI': '10.1016/S0140-6736(20)31030-8',
'volume': '395',
'author': 'FJ de Abajo',
'year': '2020',
'unstructured': 'de Abajo, F. J. et al. Use of renin–angiotensin–aldosterone system '
'inhibitors and risk of COVID-19 requiring admission to hospital: a '
'case-population study. Lancet 395, 1705–1714 (2020).',
'journal-title': 'Lancet'},
{ 'key': '19145_CR49',
'doi-asserted-by': 'publisher',
'first-page': '198',
'DOI': '10.1111/his.14134',
'volume': '77',
'author': 'T Menter',
'year': '2020',
'unstructured': 'Menter, T. et al. Postmortem examination of COVID-19 patients reveals '
'diffuse alveolar damage with severe capillary congestion and variegated '
'findings in lungs and other organs suggesting vascular dysfunction. '
'Histopathology 77, 198–209 (2020).',
'journal-title': 'Histopathology'}],
'container-title': 'Nature Communications',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.nature.com/articles/s41467-020-19145-6.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41467-020-19145-6',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.nature.com/articles/s41467-020-19145-6.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 12, 6]],
'date-time': '2022-12-06T01:48:02Z',
'timestamp': 1670291282000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41467-020-19145-6'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2020, 10, 28]]},
'references-count': 49,
'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2020, 12]]}},
'alternative-id': ['19145'],
'URL': 'http://dx.doi.org/10.1038/s41467-020-19145-6',
'relation': { 'has-preprint': [ { 'id-type': 'doi',
'id': '10.1101/2020.05.08.20092866',
'asserted-by': 'object'}]},
'ISSN': ['2041-1723'],
'subject': [],
'container-title-short': 'Nat Commun',
'published': {'date-parts': [[2020, 10, 28]]},
'assertion': [ { 'value': '18 May 2020',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '30 September 2020',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '28 October 2020',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': 'The authors declare no competing interests.',
'order': 1,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}],
'article-number': '5453'}
