Virus-Host Interactions in Foot-and-Mouth Disease Virus Infection

Abstract

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals, which has been regarded as a persistent challenge for the livestock industry in many countries. Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD that can spread rapidly by direct and indirect transmission. FMDV is internalized into host cell by the interaction between FMDV capsid proteins and cellular receptors. When the virus invades into the cells, the host antiviral system is quickly activated to suppress the replication of the virus and remove the virus. To retain fitness and host adaptation, various viruses have evolved multiple elegant strategies to manipulate host machine and circumvent the host antiviral responses. Therefore, identification of virus-host interactions is critical for understanding the host defense against virus infections and the pathogenesis of the viral infectious diseases. This review elaborates on the virus-host interactions during FMDV infection to summarize the pathogenic mechanisms of FMD, and we hope it can provide insights for designing effective vaccines or drugs to prevent and control the spread of FMD and other diseases caused by picornaviruses.

Keywords: FMDV; immune dysfunction; interactions; pathogenesis; viral infection.

Figure 1

The viral genome structure of foot-and-mouth disease virus (FMDV). The viral genome contains a 5′-untranslated region (5′UTR), a large open reading frame (ORF) including the L, VP4, VP2, VP3, VP1, 2A, 2B, 2C, 3A, 3B(3B1, 3B2, and 3B3), 3C, and 3D coding regions, and a 3′UTR.

Figure 2

Immune cell dysfunction caused by foot-and-mouth disease virus (FMDV) infection. FMDV infection blocks the activation of Toll-like receptors (TLRs) pathways in dendritic cells. It also reduces the expression of MHC II molecules on the surface of dendritic cells and macrophages, leading to the decreased antigen presentation activity, which in turn blocking the activation of T cells. Moreover, FMDV infection induces the secretion of IL-10, and reduces the expression of MHC I molecules, suppressing the adaptive immune response mediated by T cells. As infection progresses, FMDV damages the cells that secrete IL-2, IL-12, IL-15, and IL-18, thus limiting NK cell activation and inhibiting the secretion of IFN-γ and perforin. The dysfunction of these immune cells during viral infection provides a favorable environment for multiplication of progeny virus.

Figure 3

Schematic representation showing the interaction between foot-and-mouth disease virus (FMDV) viral proteins and host proteins in the innate immune system. FMDV invades into host cells through integrin receptors, the viral cytosolic RNAs and endosomal RNAs are recognized by RIG-I-like receptors (RLRs) [retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5] and Toll-like receptors (TLRs) (TLR3 and TLR7/8), triggering a signaling cascade, and inducing the production of interferons (IFNs) and cytokines to initiate direct or indirect antiviral responses. RIG-I and MDA-5 expose their CARD domains and then interact with the CARD of mitochondrial antiviral signaling protein (MAVS), while TLR3 and TLR7/8 interact with TRIF and MyD88, respectively. The recruited molecules TANK and TRAF3/6 subsequently activate different pathways through recruiting the IKK-α/β or TBK1/IKK-ϵ. IKK-α/β activates IκBα by phosphorylating it, and the phosphorylated IκBα is ubiquitinated and degraded by the proteasomes, allowing the release of p50/p65. The released p50/p65 translocates to the nucleus and binds to the specific gene promoters, initiating the expression of various proinflammatory cytokines. TBK1 phosphorylates IRF3 or IRF7, and induces the IRF3-IRF3 or IRF3-IRF7 dimerization. The IRF3-IRF3 or IRF3-IRF7 dimers transport to the nucleus, then bind to the IFNs promoters and initiate IFNs secretion. The synthesized IFNs bind to their specific receptors on the cell surface, activating TYK2 and JAK1 to induce STAT1/2 forming the phosphorylated heterodimers, which then interact with IRF9 and serves as a transcription factor complex (also known as ISGF3). The ISGF3 enters the nucleus and induces the expression of ISGs. Multiple virulence factors of FMDV target the components of the host innate immune system, thereby inhibiting the host antiviral responses. L^pro, as a multifunctional protein, cleaves LGP2, acts as a deubiquitinating enzyme (DUB) to inhibit the ubiquitination of RIG-I, TRAF3/6, and TBK1, decreases the accumulation of p65, and hinders IRF3/7 phosphorylation. 3C^pro, as an important virulent factor as well, cleaves NEMO, inhibits the binding of STAT1/2 to IRF9, induces the degradation of PKR through the lysosomal pathway. 3A interacts with DDX56 to inhibit the phosphorylation of IRF3. VP1 interacts with sorcin, activating STAT3 to inhibit IκBα phosphorylation. VP3 inhibits the expression of MAVS, and interacts with JAK1 to inhibit STAT1/2 phosphorylation and dimerization. In contrast, several host restriction factors also interact with the components in the pathways to enhance host antiviral response and suppress FMDV replication. Sec62 interacts with MAVS and TRAF3 to stabilize their status. EGR1 and ESD promote the phosphorylation of TBK1 and IRF3, respectively, to enhance type I IFN production and IFN response.

Figure 4

The interplay between autophagy and apoptosis, and the regulation of autophagy and apoptosis by foot-and-mouth disease virus (FMDV) infection. Autophagy and apoptosis are essential physiological responses to maintain cell and body homeostasis. The relationship between autophagy and apoptosis is complicated under various stimulus, they promote the activation of each other in some conditions, but also inhibit each other in in some special conditions. Bcl-2 binds to Beclin-1 and separates Beclin-1 from Class III P13K complex, leading to the inhibition of autophagy. Caspase-3 inhibits autophagy and activates apoptosis by cleavage of Beclin-1. Caspase-6 disrupts autophagy by induction of ATG5 and Beclin-1 cleavage. The interaction between caspase-9 and ATG7 promotes the formation of LC3-II and activation of autophagy, but inhibits the caspase-9 apoptotic activity. The cleaved ATG5 catalyzed by cathepsin migrates from cytoplasm to mitochondria, and then interacts with Bcl-XL to promote the release of Ccyt-C and activation of caspases. Uncoupled ATG12 positively regulates mitochondrial apoptosis by binding to Bcl-2 and inhibits the function of Bcl-2. ATG12 promotes the up-regulation of Bax and enhances the release of Cyt-C. FMDV infection is highly associated with autophagy and apoptosis. FMDV VP1 interacts with the integrin receptor, which activates the caspases 3, 8 and 9, and down-regulates the expression of Bcl 2, leading to the release of Cyt-C, and finally induces the apoptosis. VP1 colocalizes with LC3 to induce the formation of LC3 punctate, contributing to autophagy and promoting FMDV replication. FMDV 3C^pro degrades ATG5-ATG12 and suppresses the occurrence of autophagy. FMDV activates PKR-like ER kinase (PERK) pathway and promotes the phosphorylation of eIF2α, and then induces the expression of autophagy gene, resulting in the activation of autophagy that promotes the multiplication of FMDV. The interaction between Beclin-1 and 2C prevents the fusion of autophagosomes with lysosomes which leads to the inhibition of autophagy. FMDV 2B protein inserts itself into the endoplasmic reticulum (ER), acting as an ion channel protein that forms a hole in the ER, which damages the homeostasis of Ca²⁺ and affects the mature of autophagosome membrane.