Figure 5: Schematic diagram showing the induction of cytokine dysregulation in severe influenza virus infection. Human infection with influenza viruses with a NS capable of suppressing pre-transcriptional IRF-3-induced IFN-β production (1918PV, 2009PV, H5N1 and H7N9) allows these influenza viruses to proliferate rapidly during the stealth phase of influenza infection.This enhanced viral replication results in an accumulation of endosomal haemagglutinin (HA) and double-stranded RNA (dsRNA). The endosomal HA activates NF-κB via the production of ROS through endoplasmic reticulum overload (ER-overload). ROS enhances TLR3 induced NFκB activation in reaction to an accumulated endosomal viral dsRNA. Profound activation of NFκB by accumulated endosomal HA and dsRNA results in cytokine dysregulation. Since NFκB activation is a prerequisite for influenza-induced cytokine dysregulation, blockade of NF-κB activation by NAC, paracetamol and COX-2 inhibitors leads to suppression of cytokine dysregulation in influenza infection.