1. Computational and Systems Biology
  2. Medicine
Download icon

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
Short Report
  • Cited 70
  • Views 148,587
  • Annotations
Cite this article as: eLife 2020;9:e59177 doi: 10.7554/eLife.59177

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.

Metrics

  • 148,587
    Page views
  • 7,802
    Downloads
  • 70
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

  1. Further reading

Further reading

    1. Cell Biology
    2. Computational and Systems Biology
    Ina Lantzsch et al.
    Research Article

    The female meiotic spindles of most animals are acentrosomal and undergo striking morphological changes while transitioning from metaphase to anaphase. The ultra-structure of acentrosomal spindles, and how changes to this structure correlate with such dramatic spindle rearrangements remains largely unknown. To address this, we applied light microscopy, large-scale electron tomography and mathematical modeling of female meiotic C. elegans spindles undergoing the transition from metaphase to anaphase. Combining these approaches, we find that meiotic spindles are dynamic arrays of short microtubules that turn over on second time scales. The results show that the transition from metaphase to anaphase correlates with an increase in the number of microtubules and a decrease in their average length. Detailed analysis of the tomographic data revealed that the length of microtubules changes significantly during the metaphase-to-anaphase transition. This effect is most pronounced for those microtubules located within 150 nm of the chromosome surface. To understand the mechanisms that drive this transition, we developed a mathematical model for the microtubule length distribution that considers microtubule growth, catastrophe, and severing. Using Bayesian inference to compare model predictions and data, we find that microtubule turn-over is the major driver of the observed large-scale reorganizations. Our data suggest that in metaphase only a minor fraction of microtubules, those that are closest to the chromosomes, are severed. The large majority of microtubules, which are not in close contact with chromosomes, do not undergo severing. Instead, their length distribution is fully explained by growth and catastrophe alone. In anaphase, even microtubules close to the chromosomes show no signs of cutting. This suggests that the most prominent drivers of spindle rearrangements from metaphase to anaphase are changes in nucleation and catastrophe rate. In addition, we provide evidence that microtubule severing is dependent on the presence of katanin.

    1. Cell Biology
    2. Computational and Systems Biology
    James Oliver Patterson et al.
    Research Article

    Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth, and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell-size homeostasis.