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. 2021 Oct 20;13(11):2116. doi: 10.3390/v13112116

Figure 1.

Figure 1

NF-κB and IRF signaling in response to mosquito-borne flavivirus infection and their antagonism in humans. Following viral infection, human cells recognize pathogen-associated molecular patterns (PAMPs) such as viral RNA through pattern recognition receptors (PRRs) that include membrane-bound TLRs such as TLR-3 and -7 and cytoplasmic members of the RIG-I-like receptor (RLR) family, including RIG-I and melanoma-differentiation-associated protein 5 (MDA5) [24,25]. In TLR signaling, TLR-3 and -7 detect double-stranded and single-stranded viral RNAs, respectively. Activated TLR-3 and -7 signal through the adaptor proteins Toll/interleukin receptor (TIR)-domain-containing adapter-including interferon (IFN)-β (TRIF) and myeloid differentiation primary response 88 (MyD88), respectively. On the other hand, RLR signaling is activated once double-stranded RNAs (dsRNAs) are sensed by RIG-I and MDA5, which, in turn, allows these receptors to bind the mitochondrial antiviral signaling (MAVS) protein through 14-3-3ε [26]. In addition, the cytosolic sensor cGAS is able to detect mosquito-borne flaviviruses as they disrupt mitochondrial morphodynamics, leading to the release of mitochondrial DNA that acts as a ligand for the activation of the cGAS-STING pathway [27,28]. cGAS induces the production of cGAMP which then binds to STING. Taken together, signaling through TRIF, MyD88, MAVS, and STING leads to the activation of different signaling molecules, including receptor-interacting protein (RIP)-1, NF-κB essential modular (NEMO), downstream kinases such as Tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), I-kappa-B-kinase ε (IKKε), and the IKK-αβγ complex, which subsequently activate transcription factors that include NF-κB, IRF3, and/or IRF7 [29,30,31]. Consequently, NF-κB, IRF3, and/or IRF7 are translocated to the nucleus where they elicit the production and release of proinflammatory cytokines and type I IFN, respectively [32,33]. However, virus-encoded antagonists of mosquito-borne flaviviruses (DENV in purple, ZIKV in green, WNV in light blue, JEV in orange, YFV in black) are able to block these pathways. See main text for details.