The Different Tactics of Foot-and-Mouth Disease Virus to Evade Innate Immunity

Figures

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  FIGURE 1. Genome organization of FMDV. A schematic representation of linear (+) stranded FMDV RNA is depicted as thin solid lines and dotted lines represent ORF. Viral genomic RNA contains elements shown at the 5′ and 3′ UTR and are represented as thin lines. The 5′UTR consists of S fragment, poly (C) tract, pseudoknots (PKs), cis-acting replicative element (cre) and internal ribosome entry site (IRES). The single ORF encodes a polyprotein and is represented in outlined-open boxes. Filled triangles, squares and diamonds indicate processing sites for 3Cpro, 2A, and Lpro, respectively. Post-translational proteolytic cleavages are shown as partial products. Asterisks describe the two AUG initiation codons. The 3′UTR consist of a short stretch of RNA and a poly (A) sequence. The P1 region encodes the structural polypeptides. The P2 and P3 regions encode the non-structural proteins associated with replication. 3B (VPg) protein is shown as covalently linked to the 5′end of the genomic RNA.

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  FIGURE 2. Innate antiviral immune responses during viral infection. Upon viral infection, viral RNA is detected by cytosolic RLRs (RIG-I, MDA-5 or LGP2) and/or membrane bound TLRs, triggering a signal transduction cascade that culminates in the transcription of innate molecules including IFN, pro-inflammatory cytokines and ISGs. Cytosolic RNA is detected by RIG-I, MDA5 and presumably LGP2. RIG-I recognizes RNAs containing 5′ppp and panhandle-like secondary structures. MDA5 recognizes dsRNA. LGP2 might regulate the functions of RIG-I and MDA5. Interaction of RIG-I and MDA5 RNA exposes their CARD domains. RIG-I is subsequently ubiquitinated with unanchored K63-linked Ub chains. MDA5 stacks along dsRNA and form helical filaments. Discrete CARD oligomers (with or without Ub) align on CARD domains of mitochondrial MAVS inducing its polymerization. Endosomal RNAs are detected by TLR3 or TLR7/8, which interact with adaptor proteins TRIF and MyD88, respectively. MyD88 uses other adaptors, IRAK1/4 to allow for interaction with TRAF proteins. Polymerization of MAVS or conformational changes on TRIF and MyD88/IRAK1/4 recruit E3 ligases, mainly TRAF3 and TRAF6. These E3 ligases synthesize poly-Ub that…

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  FIGURE 3. Foot-and-mouth disease virus modulates early stages of immune response in vivo. Upon FMDV infection and first round of replication in epithelial cells-the primary infection site-, FMDV gets in contact with cells of the innate immune response inducing functional consequences that affect the host response. FMDV interacts with different players of the immune response either as a result of lytic infection of epithelial cells and subsequent phagocytosis, and/or lytic action on damaged infected tissue or by direct infection of immune cells through a direct or an antibody-dependent internalization process in Mφ, DCs, or NK or γδ T cells. After this stage, DCs, pDCs and Mφ produce IFN and other cytokines that modulate the immune response. Possible interaction of DC, NK and γδ T cells in the innate immune response is depicted, although clear interaction is thus far not completely understood. Ultimately, after FMDV infection and replication, systemic IL-10 produced by cDCs is detected, thus directing the adaptive immune response toward a stronger humoral stimulation rather than a T-cell mediated response.