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

  1. Ivan T. Lee
  2. Tsuguhisa Nakayama
  3. Chien-Ting Wu
  4. Yury Goltsev
  5. Sizun Jiang
  6. Phillip A. Gall
  7. Chun-Kang Liao
  8. Liang-Chun Shih
  9. Christian M. Schürch
  10. David R. McIlwain
  11. Pauline Chu
  12. Nicole A. Borchard
  13. David Zarabanda
  14. Sachi S. Dholakia
  15. Angela Yang
  16. Dayoung Kim
  17. Han Chen
  18. Tomoharu Kanie
  19. Chia-Der Lin
  20. Ming-Hsui Tsai
  21. Katie M. Phillips
  22. Raymond Kim
  23. Jonathan B. Overdevest
  24. Matthew A. Tyler
  25. Carol H. Yan
  26. Chih-Feng Lin
  27. Yi-Tsen Lin
  28. Da-Tian Bau
  29. Gregory J. Tsay
  30. Zara M. Patel
  31. Yung-An Tsou
  32. Alexandar Tzankov
  33. Matthias S. Matter
  34. Chih-Jaan Tai
  35. Te-Huei Yeh
  36. Peter H. Hwang
  37. Garry P. Nolan
  38. Jayakar V. Nayak
  39. Peter K. Jackson

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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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  1. Version published to 10.1038/s41467-020-19145-6
  2. ScreenIT

    SciScore for 10.1101/2020.05.08.20092866: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: All tissue specimens and patient medical record information, including demographics, medical/social history, and medications were collected under approved Institutional Review Board (IRB) protocols in accordance with the regulations of the Research Compliance Office at the respective institutions.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    , rabbit anti-ACE2 (1:100; Abcam ab239924), rabbit anti-ACE2 (1:100; Novus NBP2-67692), goat anti-ACE2 (1:100; R&D Systems AF933)
    anti-ACE2
    suggested: None
    ImmPRESS HRP anti-rabbit, anti-mouse, or anti-goat IgG polymer detection kit (Vector Laboratories, Burlingame, CA) was used as the secondary antibody link for 30 minutes at room temperature.
    anti-rabbit
    suggested: None
    anti-mouse , or anti-goat IgG
    suggested: None
    anti-goat
    suggested: None
    Software and Algorithms
    SentencesResources
    Post-imaging processing was performed using ImageJ.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Figures were organized using Adobe Illustrator.
    Adobe Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)
    Images were scanned and digitized using the Aperio AT2 and viewed using Aperio Imagescope software.
    Imagescope
    suggested: (ImageScope, RRID:SCR_014311)
    Quantitation was performed in the FIJI package of ImageJ open source software.
    FIJI
    suggested: (Fiji, RRID:SCR_002285)
    Statistical analysis: Analyses were performed with IBM SPSS 23 (IBM Corporation, Armonk, NY) and GraphPad Prism 6.0 (GraphPad Software, La Jolla, CA) software.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.08.20092866 on medRxiv