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 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.

Keywords: COVID-19; bradykinin; computational biology; human; human biology; hyaluronic acid; medicine; pathogenesis; renin-angiotensin system; systems biology.

Figure 1.. 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.

Figure 2.. 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 Ang_1-9 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 Ang_1-9 (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 Ang_1-9 further sensitizes the effects of bradykinin at BDKRB2. Other enzymes that degrade BK are also downregulated such as MME, which is meant to degrade Ang_1-9 , 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.

Figure 3.. 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.

Figure 4.. 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 Ang_1-9 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.