1. Computational and Systems Biology
  2. Medicine
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A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

  1. Michael R Garvin
  2. Christiane Alvarez
  3. J Izaak Miller
  4. Erica T Prates
  5. Angelica M Walker
  6. B Kirtley Amos
  7. Alan E Mast
  8. Amy Justice
  9. Bruce Aronow
  10. Daniel Jacobson  Is a corresponding author
  1. Oak Ridge National Laboratory, Biosciences Division, United States
  2. University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, United States
  3. University of Kentucky, Department of Horticulture, United States
  4. Versiti Blood Research Institute, Medical College of Wisconsin, United States
  5. VA Connecticut Healthcare/General Internal Medicine, Yale University School of Medicine, United States
  6. University of Cincinnati, United States
  7. Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, United States
  8. University of Tennessee Knoxville, Department of Psychology, Austin Peay Building, United States
Short Report
Cite this article as: eLife 2020;9:e59177 doi: 10.7554/eLife.59177
4 figures, 1 table, 2 data sets and 3 additional files

Figures

Functionally annotated network of genes involved in the hypertension-hypotension axis whose expression across the GTEx population is correlated and anticorrelated with the AGTR1 and AGTR2 receptors.

When ACE is downregulated and ACE2 and the BK pathway is upregulated in the lungs of COVID-19 patients it leads to the hypotension, vascular permeability, and the Bradykinin Storm that explains much of COVID-19 symptomatology. As can be seen broadly across the figure, the resulting dysfunction caused by this imbalance will likely have a significant impact on the immune response by increasing processes on the right and decreasing those on the left. Genes are hexagons, highlighted colored genes of the AGTR1 cluster are associated with vasoconstriction and their connections to other enriched features are via pink edges; green highlighted genes in the AGTR2 cluster are those associated with fluid balance and vasodilation and their connections to enriched features are shown as light green edges. Figure is made from two gene cluster input to http://toppcluster.cchmc.org using FDR cutoff of 0.05 for network output and xgmml output to Cytoscape.

Critically disrupted RAS and Bradykinin pathways in COVID-19 BAL samples.

(A) Significantly differentially expressed genes: red ovals indicate genes upregulated in COVID-19, blue are downregulated, colors are scaled to the log2-fold-change values for COVID-19. The overall effect is to shift the system to production of Ang1-9 and AGTR2-driven sensitization of BK receptors involved in pain (BDKRB1) and NO-dependent vasodilation (BDKRB2). Several points of inhibition maintain this imbalance. The suppression of NFkappaB by the virus decreases its binding to the ACE promoter and subsequent transcription (lower left). Decrease in the activation of Vitamin D and its receptor (VDR), which normally inhibits REN production, in combination with the upregulation of ACE2, increases flux of angiotensin to Ang1-9 (top left). Decrease in the expression of the SERPING1 gene, lifts suppression of FXII of the intrinsic coagulation cascade, resulting in further production of BK from kallikrein and KNG (both upregulated) (top right). BK levels are further increased because ACE, which normally degrades it, is decreased. A surge in Ang1-9 further sensitizes the effects of bradykinin at BDKRB2. Other enzymes that degrade BK are also downregulated such as MME, which is meant to degrade Ang1-9 , BK, and another important peptide Apelin (APLN). (B) The result of a hyperactive bradykinin system is vasodilation to the point of vascular leakage and infiltration of inflammatory cells.

The upregulation of hyaluronan synthases and downregulation of hyaluronidases combined with the BK-induced hyperpermeability of the lung microvasculature leads to the formation of a HA-hydrogel that inhibits gas exchange in the alveoli of COVID-19 patients.
Systemic-level effects of critically imbalanced RAS and BK pathways.

The gene expression patterns from COVID BAL samples reveal a RAS that is skewed toward low levels of ACE that result in higher levels of Ang1-9 and BK. High levels of ACE normally present in the lungs are responsible for generating system-wide angiotensin-derived peptides. As detailed in Figure 2, the Bradykinin-Storm is likely to affect major organs that are regulated by angiotensin derivatives. These include altered electrolyte balance from affected kidney and heart tissue, arrhythmia in dysregulated cardiac tissue, neurological disruptions in the brain, myalgia in muscles and severe alterations in oxygen uptake in the lung itself. Red colors indicate upregulation and blue downregulation.

Tables

Table 1
Potential therapeutic interventions, their targets, and predicted effect.
DrugTargetPredicted Effect
Danazol, StanozololSERPING1Reduce Bradykinin production
IcatibantBKB2RReduce Bradykinin signaling
EcallantideKLKB1Reduce Bradykinin production
Berinert,Cinryze,HaegardaSERPING1Reduce Bradykinin production
Vitamin DRENReduce Renin production
HymecromoneHAS1,HAS2, HAS3Reduce hyaluronan
TimbetasinTMSB4XIncrease fibrinolysis

Data availability

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
  1. 1
    NCBI Sequence Read Archive
    1. P Zhou
    (2020)
    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.
  2. 2
    NCBI BioProject
    1. D Mayhew
    (2018)
    ID PRJNA434133. Microbiome and Inflammatory Interactions in Obese and Severe Asthmatic Adults.

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