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.
Original language | English |
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Article number | e59177 |
Pages (from-to) | 1-16 |
Number of pages | 16 |
Journal | eLife |
Volume | 9 |
DOIs | |
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 |
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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 |