Figure 4.

EV71 directly influences antiviral innate immunity and inflammatory responses by targeting pattern recognition receptors (PRRs). TLRs and NOD-like receptors (NLRs) belong to PRRs that sense lipids, lipoproteins, or peptidoglycans from bacteria, fungi, or protozoa, namely pathogen-associated molecular patterns (PAMPs). Additionally, these PRRs sense bacterial and viral nucleic acids, termed damage-associated molecular patterns (DAMPs). Endosomal TLR3 and TLR7 sense dsRNA of EV71. 3C^pro inhibits TLR3-mediated type I IFN production by blocking Toll/IL-1 Receptor domain-containing adaptor inducing IFN-β (TRIF). The interaction between hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) and TAK1 regulates the ESCRT-0 complex and endosomal sorting of membrane proteins. HRS facilitates TLR7/NF-κB/p38 and TLR7/NF-κB/IRF3 signaling to produce proinflammatory cytokines and interferons during EV71 infection. Unlike TLR3 and TLR7, TLR9 senses endogenous DNA, and then mediates type I IFN production and NF-κB activation. EV71 infection also activates TLR4/myeloid differentiation primary response 88 (MyD88)-dependent NF-κB signaling, which induces multiple proinflammatory cytokines including pro-IL-1β and pro-IL-18. 3D^pro controls the assembly of the NLRP3 inflammasome that consists of pro-caspase-1 (casp1), ASC, and NLR family pyrin domain containing protein-3 (NLRP3). When activated, pro-casp1 matures into casp1 that cleaves pro-IL-1β and pro-IL-18 to become the mature IL-1β and IL-18 proteins. 2A^pro and 3C^pro can inhibit NLRP3 inflammasome activation.