SARS-CoV-2 uses ACE2 as cell entry receptors and causes downregulation of ACE2. This is followed by host pattern recognition receptors (PRRs)-mediated detection of a viral pathogen-associated molecular patterns (PAMPs) resulting in interaction of PRRs with mitochondrial antiviral-signaling protein (MAVS) that activates NF_κB through a signaling cascade involving several kinases. Activated NF_κB translocate to the nucleus and induces the transcription of pro-inflammatory cytokines: Il-6, TNF-α and IL-1β. (minor direct pathway ). Binding of SARS-CoV-2 to ACE2 is also associated with activation of TACE dimer to TACE monomer. Activated TACE induces shedding of several membrane proteins including TNF-α, IL-6Rα, TNF-αR1, TNF-αR2 and EGF receptor. TNF-α upregulates AT1R density on epithelial and endothelial cells. Cross-talk between TNF-α and Ang II contribute to mitochondrial oxidative stress, activation of PAI-1, MCP-1 and AP-1. EGF receptor activation induces hypoxia inducible factor 1 alpha (HIF-1α) activity. IL6-sILRα complex produces gp130 mediated activation of STAT3 in a variety of 1L6Rα negative cells including pericytes, endothelial cells and epithelial cells resulting in activation of NF_κB pathway. NF_κB via. downstream mediators Elk-1 and activator protein (AP-1) results in AT1R upregulation. AngII-AT1R overactivity induces a feed-forward loop of TACE activation, sustained EGFR activation and stablishes positive feedback loop of AngII-AT1R-NF_κB axis. AngII via hypoxia inducible factor 1 alpha (HIF-1α) also increases gene expression of ACE, AT1R and VEGF. Overall, positive feedforward pathways are established resulting in upregulation of ACE-AngII-AT1R, TNFα and IL6 activity mediating apoptosis and activation of pericytes, endothelial and epithelial cells and cytokine storm (major indirect pathway ). AngII mediated cytoplasmic and mitochondrial oxidative stress results in impaired mitochondrial biogenesis. AngII-AT1R activity on endothelial cells causes degranulation of weibel palade bodies with massive release of P-selectin, wVF, IL-8 and Ang2, mediators that can generate vascular phenomenon of pericyte loss, platelet aggregation and activation, complement activation, neutrophilic infiltration and NETosis resulting in macro and microvascular thrombosis of COVID-19.