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 NFκB through a signaling cascade involving several kinases (minor direct pathway). Activated NFκB translocate to the nucleus and induces the transcription of pro-inflammatory cytokines: Il-6, TNF-α and IL-1β. Binding of SARS-CoV-2 to ACE2 is also associated with activation of TACE dimer to TACE monomer. Activated TACE cleaves several membrane proteins including TNF-α, IL-6Rα, TNF-αR1 and TNF-αR2. 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 full activation of NFκB pathway. NFκB via. downstream mediators Elk-1 and activator protein (AP-1) results in AT1R upregulation. Positive feedback pathways are stablished 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).