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.
Bibliographical noteFunding Information:
We thank members of the Nolan, Nayak, Jackson, Yeh, Tsay, and Stanford Pathology laboratories for helpful discussions and technical assistance. We thank Polly Kavanaugh, Nicole Wang, Carol Valencia, Rebekah Youkhana, Alfred Machicado, Jason Irwin, Camilla Morrison, and Yuka Lee for excellent laboratory and administrative support. We are grateful to faculties of the Stanford Allergy/Immunology Division, especially Drs. Dave Lewis, Yael Gernez, Sean McGhee, and Anne Liu for guidance and accommodations made for Ivan T. Lee’s protected research time. We thank Mark Kittisopikul for informal discussion on statistical analysis. We further thank Dr. Ekkehard Hewer, Dr. José Galván, and Sandrine Ruppen (Institute of Pathology, University of Bern, Switzerland) for help with creating tissue microarrays. This work was supported by the Parker Institute for Cancer Immunotherapy (G.P.N.), Food and Drug Administration (HHSF223201610018C and DSTL/AGR00980) (G.P.N.), Fast Grant Funding for COVID-19 Science (G.P.N. and P.K.J.), the Botnar Research Centre for Child Health Emergency Response to COVID-19 Grant (S.J., C.M.S., D.R.M., G.P.N., M.S.M., and A. T.), a Bill and Melinda Gates Foundation COVID-19 Pilot Award (S.J., D.R.M., and G.P. N.), the National Institutes of Health 1R01AI149672-01 (G.P.N.), U54-CA209971 (G.P. N.), P30DK116074 (P.K.J.), the Rachford & Carlotta A. Harris Endowed Chair (G.P.N.), California Institute for Regenerative Medicine (DISC2-09637) (J.V.N.), Defense Advanced Research Project Agency (HR001118S0037-PREPARE-FP-001) (J.V.N.), The Stanford Initiative to Cure Hearing Loss (SICHL) (P.A.G. and J.V.N.), The Operndorf Foundation (P.A.G. and J.V.N.), The PDev Foundation (J.V.N.), Stanford Translational Research and Applied Medicine (TRAM) Pilot Grant (I.T.L.), Thrasher Research Fund Early Career Award (I.T.L.), Stanford Maternal and Child Health Research Institute (MCHRI) Clinical (MD) Trainee Support Award (I.T.L., Ernest and Amelia Gallo Endowed Postdoctoral Fellow), Leukemia & Lymphoma Society Career Development Program (S.J.), and the Swiss National Science Foundation (C.M.S., P400PM_183915).
© 2020, The Author(s).