A Comprehensive Review of the Immunological Response against Foot-and-Mouth Disease Virus Infection and Its Evasion Mechanisms

Abstract

Foot-and-mouth disease (FMD) is a highly contagious viral disease, which has been reported for over 100 years, and against which the struggle has lasted for the same amount of time. It affects individuals from the order Artiodactyla, such as cattle, swine, sheep, wild animals from this order, and a few non-cloven hoofed species, such as mice and elephants. FMD causes large-scale economic losses for agricultural production systems; morbidity is almost 100% in an affected population, accompanied by a high mortality rate in young animals due to myocarditis or an inability to suckle if a mother is ill. The aetiological agent is an Aphthovirus from the family Picornaviridae, having seven serotypes: A, O, C, SAT1, SAT2, SAT3, and Asia 1. Serotype variability means that an immune response is serospecific and vaccines are thus designed to protect against each serotype independently. A host's adaptive immune response is key in defence against pathogens; however, this virus uses successful strategies (along with most microorganisms) enabling it to evade a host's immune system to rapidly and efficiently establish itself within such host, and thus remain there. This review has been aimed at an in-depth analysis of the immune response in cattle and swine regarding FMD virus, the possible evasion mechanisms used by the virus and describing some immunological differences regarding these species. Such aspects can provide pertinent knowledge for developing new FMD control and prevention strategies.

Keywords: foot-and-mouth-disease virus; immune evasion mechanism; immune response.

Figure 1

A scheme showing Foot-and-mouth disease virus (FMDV) entry to target cells. Adapted [36].

Figure 2

Diagram of the FMDV genome, viral polypeptide processing, and structural and non-structural protein formation. Adapted [14,36,42,43].

Figure 3

Ideal host immune response to FMDV. Anatomical, physiological, endocytic, phagocytic, and inflammatory barriers initially react against FMDV: the mucosity produced by respiratory tract ciliated cells retain part of the viral particles; neutrophils (Neu), eosinophils, dendritic cells (DC), macrophages (M), and cytotoxic (CTL) and natural killer (NK) lymphocytes, complement proteins and other inflammation mediators begin to act. Stress signals trigger gdT in tissue to secrete cytokines, thereby attracting DCs, macrophages and B-lymphocytes which act as antigen-presenting cells (APC). A greater amount of DCs and macrophages phagocyte FMDV, process it and express the antigens on its membrane with major histocompatibility complex (MHC) intervention, these being recognized by Th-lymphocytes, giving rise to Th1 and Th2 differentiation. The cytokines secreted by these cells stimulate macrophage, neutrophil, DC, natural killer cell, CTL, and B-lymphocyte proliferation and differentiation. The virus’ soluble antigens (SA) bind to B-cell Abs simultaneously with antigen presentation by antigen-presenting cells; this is followed by these cells becoming transformed into plasma cells secreting IgM, IgG, and IgA, where IgM and IgG opsonize viral particles, stimulating phagocytosis, neutralising and activating antibody-dependent cellular cytotoxicity (ADCC), whilst IgA contributes to retaining viral particles in the mucosa, avoiding infection of epithelial cells. Infected target cells also express viral proteins from their cytosol along with MHC class I intervention and CTL are recognized, enabling Th1 stimulus to induce infected cell apoptosis. Antigen binding to B- and T-lymphocyte receptors triggers their activation; this is mediated by a complex cytokine network (interleukins (IL), tumor necrosis factors (TNF), interferons (IFN), colony-stimulating factors (CSF) and chemokines) connecting cells to each other, regulating their function by inducing or supressing their synthesis or that of other cytokines and their receptors. Activated lymphocytes multiply by clonal expansion, producing two types of cell: effector and memory cells. Effector cells have a short lifespan and effect and regulate response to a pathogen. Memory cells live for a long time, increasing immune response speed and intensity if the same pathogen is found again.

Figure 4

Foot-and-mouth disease virus mechanisms for evading an immune response. (A) FMDV enters the airways, taking advantage of its small size which seems to enable it to evade the airways’ lysozymes and lactoferrins. It enters the epithelial cells by receptor-mediated endocytosis: i.e., integrins and heparan sulphate (HS). Capsid protein viral polypeptide 1 (VP1) is the most antigenic viral protein; a region in this polypeptide’s G-H loop consists of 140 to 160 aa; it has been identified as the predominant epitope stimulating nAb production by B-cells. Comparing the structures of various FMDV serotypes has shown that the main differences regarding formation are produced in VP1, VP2, and VP3 loop and C-terminal region, thereby contributing to the virus’ antigenic variation. Dynamic simulations of FMDV’s molecular structure have revealed that the G-H loop protrudes from the capsid’s surface and actively fluctuates as a tentacle in its natural state, suggesting that such “flexibility” could ensure the virus’ correct binding to Abs and cell receptors. The VP2 polypeptide’s Cys 130 region of the virus’ O serotype could covalently bind to VP1 Cys 134 region using a disulphide bond for increasing the extent of variation in the VP1 loop. (B) The endosome’s low pH promotes the viral genome’s stripping and release which becomes translocated to host cell cytosol. Positive-sense genomic RNA (gRNA) functions as messenger RNA (mRNA); it has the VPg protein at the 5′ extreme, followed by the 5UTR region with the PolyC region and internal ribosome entry site (IRES) which binds to the ribosomes, followed by the open reading frame (ORF). The 3UTR region and the PolyA tail are at the 3′ extreme. Proteinase L (L^pro) and P1, P2, and P3 polypeptides are released by viral polyprotein processing by proteolytic cleavage; P1 encodes structural proteins VP1, VP2, VP3, and VP4 which assemble to form the viral capsid. P2 encodes three non-structural proteins: 2A, 2B, and 2C. P3 encodes four non-structural proteins: 3A, 3B, 3C, and 3D. 2B and 2C expression is related to blocking host cell protein secretion and greater permeability of their plasmatic membrane. L^pro promotes rapid replication of the viral genome, inactivates (eIF-4G) host cell mRNA translation, inhibits host cell protein synthesis, blocks IFNα and IFNβ expression and promotes viral protein synthesis thereby reducing host cell ability to develop an antiviral response. Viral proteins P3C^pro or 3C^pro are related to cell protein cleavage in infected cell cytoplasm, induce H3 cleavage, lowering host cell mRNA levels. When 3CD or 3Cpro are found in host cell nucleus this inhibits H3, reducing host cell mRNA synthesis even more so. This could also impede IFN I signalling by altering STAT 1 and STAT 2 nuclear translocation, affecting antiviral effectors and immunostimulatory genes. (C). It has been estimated that FMDV also affects the mechanism for antigen presentation by DCs and monocytes; these cells increase IL-10 production, reduce MHC II expression which decreases antigen processing by these cells.