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. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. 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.
Document Type
Article
Publication Date
7-7-2020
Digital Object Identifier (DOI)
https://doi.org/10.7554/eLife.59177
Funding Information
Oak Ridge National Laboratory (Laboratory Directed Research and Development Program)
- Michael R Garvin
- J Izaak Miller
- Erica T Prates
- Daniel Jacobson
U.S. Department of Energy (National Virtual Biotechnology Laboratory)
- Michael R Garvin
- Christiane Alvarez
- J Izaak Miller
- Erica T Prates
- Angelica M Walker
- Daniel Jacobson
National Institutes of Health (U24 HL148865)
- Bruce Aronow
Related Content
FASTQ files are available from the NCBI Sequence Read Archive (PRJNA605983 and PRJNA434133) https://www.ncbi.nlm.nih.gov/sra Leinonen, 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:
Zhou P (2020) NCBI Sequence Read Archive ID PRJNA605983. Discovery and characterization of a novel human coronavirus from five patients at the early stage of the Wuhan seafood market pneumonia virus outbreak. https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA605983
Mayhew D (2018) NCBI BioProject ID PRJNA434133. Microbiome and Inflammatory Interactions in Obese and Severe Asthmatic Adults. https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA434133
Repository Citation
Garvin, Michael R.; Alvarez, Christiane; Miller, J. Izaak; Prates, Erica T.; Walker, Angelica M.; Amos, B. Kirtley; Mast, Alan E.; Justice, Amy; Aronow, Bruce; and Jacobson, Daniel, "A Mechanistic Model and Therapeutic Interventions for COVID-19 Involving a RAS-Mediated Bradykinin Storm" (2020). Horticulture Graduate Research. 1.
https://uknowledge.uky.edu/horticulture_gradpub/1
Supplementary file 1: Patient metadata. https://cdn.elifesciences.org/articles/59177/elife-59177-supp1-v3.xlsx
elife-59177-supp2-v3.xlsx (40 kB)
Supplementary file 2: Sample PCA, TPM and Differential Gene Expression Values for genes in this paper. https://cdn.elifesciences.org/articles/59177/elife-59177-supp2-v3.xlsx
elife-59177-transrepform-v3.pdf (221 kB)
Transparent reporting form. https://cdn.elifesciences.org/articles/59177/elife-59177-transrepform-v3.pdf
Notes/Citation Information
Published in eLife, v. 9, e59177.
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.