Molecular pathways involved in COVID-19 and potential pathway-based therapeutic targets

Abstract

Deciphering the molecular downstream consequences of severe acute respiratory syndrome coronavirus (SARS-CoV)- 2 infection is important for a greater understanding of the disease and treatment planning. Furthermore, greater understanding of the underlying mechanisms of diagnostic and therapeutic strategies can help in the development of vaccines and drugs against COVID-19. At present, the molecular mechanisms of SARS-CoV-2 in the host cells are not sufficiently comprehended. Some of the mechanisms are proposed considering the existing similarities between SARS-CoV-2 and the other members of the β-CoVs, and others are explained based on studies advanced in the structure and function of SARS-CoV-2. In this review, we endeavored to map the possible mechanisms of the host response following SARS-CoV-2 infection and surveyed current research conducted by in vitro, in vivo and human observations, as well as existing suggestions. We addressed the specific signaling events that can cause cytokine storm and demonstrated three forms of cell death signaling following virus infection, including apoptosis, pyroptosis, and necroptosis. Given the elicited signaling pathways, we introduced possible pathway-based therapeutic targets; ADAM17 was especially highlighted as one of the most important elements of several signaling pathways involved in the immunopathogenesis of COVID-19. We also provided the possible drug candidates against these targets. Moreover, the cytokine-cytokine receptor interaction pathway was found as one of the important cross-talk pathways through a pathway-pathway interaction analysis for SARS-CoV-2 infection.

Keywords: COVID-19; Drug targets; Molecular pathway; SARS-CoV-2.

Graphical abstract

Fig. 1

Schematic representation of possible molecular mechanism involved in Covid-19. ACE2 deficiency is occurred in SARS-CoV-2 infection, due to binding of S protein to this receptor as well as shedding of it by ADAM17. ACE2 converts Ang II, a peptide hormone involved in pro-inflammatory activities to Ang 1–7. Binding of Ang 1–7 to Mas receptor indicates various beneficial effects in the human body including vasodilation, anti-thrombotic, anti-fibrotic, and anti-inflammatory. Depletion of ACE2 leads to over-production of Ang II and its binding to AT1R causes activation of ADAM17 protease. ADAM17 can cleave membrane-anchored proteins and immunological cytokines such as IL-6, TNF-α and EGFR ligands, which modulation of them triggers pro-inflammatory pathways. Also, ADAM17 cleavages Notch-ligand complex then the Notch intracellular domain is cleaved by the γ-secretase complex, resulting its release and transfer to the nucleus and the transcriptional activation of Notch target genes such as inflammatory cytokines and furin. Des-arg⁹ bradykinin (DABK) is a biological substrate of ACE2 in the lungs and deficiency of ACE2 led to stimulation of bradykinin receptor (B1R) by DABK and releasing of the pro-inflammatory chemokines. Besides, activation of B1R can cause AT1R upregulation and ADAM17 stimulation lead to transactivation of EGFR. On the other hand, Ang II stimulation can significantly increase the expression of B1R suggesting possible cross-talk between AT1R and B1R in SARS-CoV-2 infection. Created with BioRender.

Fig. 2

Schematic representation of “cytokine storm: the cytokine storm mediates the harmful effects leading to multi-organ damage.

Fig. 3

IL-6 Signaling (Classical and Trans): IL-6 signaling leads to both anti-inflammatory and inflammatory cascades by classical and trans-signaling pathways. Classical IL-6 signaling is anti-inflammatory through IL-6 binding to the transmembrane cell surface receptor. IL-6 trans-signaling is thought to be pro-inflammatory pathway. In this state, IL-6/IL-6R complex bind to the gp130 on cell surface. The both of classical and trans-signaling through IL-6/IL-6R/gp130 complex activates cellular pathways by JAK/STAT, PI3K/AKT, and MAPK pathways.

Fig. 4

Toll-like receptor signaling pathway in response to SARS-CoV-2. Created with BioRender.

Fig. 5

The canonical and non-canonical NF-κB signaling pathways in the inflammatory response of COVID-19. Created with BioRender.

Fig. 6

Proposed cell death signaling mechanisms following SARS-CoV-2 infection, including apoptosis, pyroptosis, and necroptosis. The 3a protein can trigger apoptosis through the extrinsic pathway and death receptors. Pyroptosis can occur following response to S protein or to excessive Ang II activation by the AT1R in the hematopoietic stem/progenitor cells (HSPCs). The 3a protein may also trigger the pyroptosis signaling, similar to the SARS-CoV 3a protein. The RIPK3-mediated necroptosis can be another cell death signaling that the activation of RIPK3 by 3a can induce necroptosis, in an MLKL-independent manner. Created with BioRender.

Fig. 7

Pathway interaction network representing the cross-talk among COVID-19 related pathways, 22 pathways with non-cross-talk genes and cross-talk genes (561 genes). The cross-talk genes are presented in orange colors. The cytokine-cytokine receptor interaction pathway (blue label) was found as a high significant pathway with the 197 cross-talk genes (of 561). (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)