Fig. 3

The diagrammatic representation of Flavivirus NS1 and its interacting partners. 1-The infected cell releases the virion particles and infects the endothelial cells via several putative receptors present on cell surfaces, 2-3-The secreted and membrane-bound NS1 interacts with several host immune cells like, Macrophages, Basophils, Monocytes and Platelets; along with IgG and IgM anti-NS1 Antibodies produce during Flaviviral infection, 4-6-The immune complex (the anti-NS1 Abs and sNS1) activates the Fc-γ receptor present on those immune cells and release the vasoactive cytokines, which further increases the vascular permeability, 7-The sNS1 efficiently interacts with IgM anti-NS1 antibodies and inhibits the classical pathway of complement system, 8-The sNS1 activates the Toll-like receptors like2,3,4,6 and 7 present on cell surface or within endosomes of cell which further releases the inflammatory responses and disrupts vascular integrity, 9-sNS1 associates with factor H of complement system and inhibits the membrane attack complex (MAC) formation, thus inhibiting the alternative pathway of complement system, 10-The binding of sNS1 to clusterin protein activates the formation of C5b-9 and SC5b-9 formation which increases the cytokine storm, 11-Also, anti-NS1 antibodies activate the platelet aggregation and/or Antibody-independent phagocytosis, which further aggravates the situation, 12-The NS1-C1 interaction not only breakdown C4 into C4a and C4b but also interacts with C4BP, a recurring protein on infected cell and inhibits the aggregation of C3 and C4b on infected cell and prevent the MAC formation which ultimately blocks the classical and lectin pathway,13-The RIG-1 and MDA-5 helicases recognizes the single and double stranded RNAs and increases the activation of inflammatory and antiviral cytokines