A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

  1. Mike R Garvin
  2. Christiane Alvarez
  3. J Izaak Miller
  4. Erica T Prates
  5. Angelica M Walker
  6. B Kirtley Amos
  7. Alan E Mast
  8. Amy Justice
  9. Bruce Aronow
  10. Daniel Jacobson  Is a corresponding author
  1. Oak Ridge National Laboratory, United States
  2. University of Tennessee Knoxville, United States
  3. University of Kentucky, United States
  4. Medical College of Wisconsin, United States
  5. Yale University, United States
  6. Cincinnati Children's Hospital Research Foundation, United States

Abstract

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS, that produces the nonapeptide angiotensin1-9 from angiotensin I. Bradykinin is a potent, but often forgotten, part of the vasopressor system that induces hypotension and vasodilation 1, and is regulated by ACE and enhanced by angiotensin1-9 2. Here we perform a completely new analysis on gene expression data from cells of bronchoalveolar lavage samples from COVID-19 patients that were used to sequence the virus, but the host information was discarded 3. Comparison with lavage samples from controls identify a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin (REN) , angiotensin (AGT), key RAS receptors (AGTR2, AGTR1), kinogen (KNG) and the kallikrein enzymes (KLKB1, many of KLK-1-15) that activate it, and both bradykinin receptors (BDKRB1, BDKRB2). This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

Data availability

FASTQ files are available from the NCBI Sequence Read Archive (PRJNA605983 and PRJNA434133)https://www.ncbi.nlm.nih.gov/sraLeinonen, R., Sugawara, H., Shumway, M. and International Nucleotide Sequence Database Collaboration, 2010. The sequence read archive. Nucleic acids research, 39(suppl_1), pp.D19-D21.

The following data sets were generated

Article and author information

Author details

  1. Mike R Garvin

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Christiane Alvarez

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. J Izaak Miller

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Erica T Prates

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Angelica M Walker

    The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee Knoxville, Knoxville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. B Kirtley Amos

    Horticulture, University of Kentucky, Lexington, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alan E Mast

    Versiti Blood Research Institute, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Amy Justice

    School of Medicine, Yale University, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Bruce Aronow

    Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Jacobson

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    For correspondence
    jacobsonda@ornl.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9822-8251

Funding

Oak Ridge National Laboratory (LOIS:10074)

  • Mike R Garvin
  • J Izaak Miller
  • Erica T Prates
  • Daniel Jacobson

U.S. Department of Energy (National Virtual Biotechnology Laboratory)

  • Mike R Garvin
  • Christiane Alvarez
  • J Izaak Miller
  • Erica T Prates
  • Angelica M Walker
  • Daniel Jacobson

National Institutes of Health (U24 HL148865)

  • Bruce Aronow

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank L van de Veerdonk, Radboud University Medical Center, Netherlands

Publication history

  1. Received: May 21, 2020
  2. Accepted: July 6, 2020
  3. Accepted Manuscript published: July 7, 2020 (version 1)
  4. Accepted Manuscript updated: July 8, 2020 (version 2)
  5. Version of Record published: August 6, 2020 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Mike R Garvin
  2. Christiane Alvarez
  3. J Izaak Miller
  4. Erica T Prates
  5. Angelica M Walker
  6. B Kirtley Amos
  7. Alan E Mast
  8. Amy Justice
  9. Bruce Aronow
  10. Daniel Jacobson
(2020)
A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm
eLife 9:e59177.
https://doi.org/10.7554/eLife.59177
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