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, 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.
-
Microbiome and Inflammatory Interactions in Obese and Severe Asthmatic AdultsNCBI Sequence Read Archive, PRJNA434133.
Article and author information
Author details
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
- Frank L van de Veerdonk, Radboud University Medical Center, Netherlands
Publication history
- Received: May 21, 2020
- Accepted: July 6, 2020
- Accepted Manuscript published: July 7, 2020 (version 1)
- Accepted Manuscript updated: July 8, 2020 (version 2)
- 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
-
- 153,285
- Page views
-
- 8,126
- Downloads
-
- 197
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Medicine
- Microbiology and Infectious Disease
- Epidemiology and Global Health
- Immunology and Inflammation
eLife has published articles on a wide range of infectious diseases, including COVID-19, influenza, tuberculosis, HIV/AIDS, malaria and typhoid fever.
-
- Computational and Systems Biology
MicroRNAs (miR), as important epigenetic control factors, reportedly regulate wound repair. However, our insufficient knowledge of clinically relevant miRs hinders their potential therapeutic use. For this, we performed paired small and long RNA-sequencing and integrative omics analysis in human tissue samples, including matched skin and acute wounds collected at each healing stage and chronic nonhealing venous ulcers (VUs). On the basis of the findings, we developed a compendium (https://www.xulandenlab.com/humanwounds-mirna-mrna), which will be an open, comprehensive resource to broadly aid wound healing research. With this first clinical, wound-centric resource of miRs and mRNAs, we identified 17 pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. Intermeshing regulatory networks controlled by these miRs revealed their high cooperativity in contributing to chronic wound pathology characterized by persistent inflammation and proliferative phase initiation failure. Furthermore, we demonstrated that miR-34a, miR-424, and miR-516, upregulated in VU, cooperatively suppressed keratinocyte migration and growth while promoting inflammatory response. By combining miR expression patterns with their specific target gene expression context, we identified miRs highly relevant to VU pathology. Our study opens the possibility of developing innovative wound treatment that targets pathologically relevant cooperating miRs to attain higher therapeutic efficacy and specificity.