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

• DOI: 10.7554/elife.59177
• Publication Date: 2020-07-07T12:00:24Z
• Authors: 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
• Keywords: Male; Angiotensins; QH301-705.5; Science; Pneumonia, Viral; renin-angiotensin system; Peptidyl-Dipeptidase A; Bradykinin; Renin-Angiotensin System; Betacoronavirus; 03 medical and health sciences; hyaluronic acid; Renin; Humans; Biology (General); Pandemics; 0303 health sciences; SARS-CoV-2; pathogenesis; Q; R; COVID-19; 3. Good health; Vasodilation; Medicine; Female; Angiotensin-Converting Enzyme 2; bradykinin; Coronavirus Infections; Transcriptome; Bronchoalveolar Lavage Fluid; Computational and Systems Biology

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.