A mechanistic model and therapeutic interventions for covid-19 involving a ras-mediated bradykinin storm

Michael R. Garvin; Christiane Alvarez; J. Izaak Miller; Erica T. Prates; Angelica M. Walker; B. Kirtley Amos; Alan E. Mast; Amy Justice; Bruce Aronow; Daniel Jacobson

doi:10.7554/eLife.59177

A mechanistic model and therapeutic interventions for covid-19 involving a ras-mediated bradykinin storm

Michael R. Garvin, Christiane Alvarez, J. Izaak Miller, Erica T. Prates, Angelica M. Walker, B. Kirtley Amos, Alan E. Mast, Amy Justice, Bruce Aronow, Daniel Jacobson

Computational and Predictive Biology

Research output: Contribution to journal › Article › peer-review

289 Scopus citations

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 angiotensin_1-9 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.

Original language	English
Article number	e59177
Pages (from-to)	1-16
Number of pages	16
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.59177
State	Published - Jul 2020

Funding

This research used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract DE-AC05-00OR22725. This research used resources of the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory. Funding for systems biology approaches was provided by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC for the US Department of Energy (LOIS:10074). Funding for diagnostics and therapeutics work was provided by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19 (which supported the work for potential points of diagnostic and therapeutic intervention), with funding provided by the Coronavirus CARES Act. This research used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract DE-AC05-00OR22725. This research used resources of the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory. Funding for systems biology approaches was provided by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC for the US Department of Energy (LOIS:10074). Funding for diagnostics and therapeutics work was provided by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19 (which supported the work for potential points of diagnostic and therapeutic intervention), with funding provided by the Coronavirus CARES Act. 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 The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Funders	Funder number
CADES
DOE Office of Science
Data Environment for Science
National Virtual Biotechnology Laboratory
Oak Ridge National Laboratory
US Department of Energy
UT-Battelle
U.S. Department of Energy	LOIS:10074
National Heart, Lung, and Blood Institute	R01HL068835
Office of Science	DE-AC05-00OR22725
Oak Ridge National Laboratory
UT-Battelle

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title = "A mechanistic model and therapeutic interventions for covid-19 involving a ras-mediated bradykinin storm",

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.",

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A mechanistic model and therapeutic interventions for covid-19 involving a ras-mediated bradykinin storm

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