Foot‐and‐Mouth Disease


Foot‐and‐mouth disease (FMD) is an economically important, highly contagious disease of cloven‐hoofed animals characterised by the appearance of vesicles (blisters) on the feet and in, and around, the mouth. The causative agent, foot‐and‐mouth disease virus (FMDV), was the first mammalian virus to be discovered. It has a ribonucleic acid (RNA) genome enclosed within a protein coat (capsid). The virus replicates very rapidly within the cytoplasm of cells. The RNA genome has to function both as a messenger RNA (mRNA) and as a template for RNA replication. The RNA encodes a single large polyprotein that is processed, by virus‐encoded proteases, to about 12 mature products (plus functionally important precursors) that are required for virus replication and assembly. Some of these viral proteins modify host cell activities to block antivirus defence systems. Thus, this small virus displays a remarkably complex array of biological activities.

Key Concepts

  • Foot‐and‐mouth disease has worldwide economic importance.
  • Foot‐and‐mouth disease virus (FMDV) is able to infect a wide range of different cloven‐hoofed animals.
  • Seven different serotypes of FMDV are known and there is considerable antigenic diversity within each serotype.
  • FMDV uses specific cell‐surface molecules (including specific integrins) as receptors to gain entry into cells.
  • The viral RNA is sufficient to initiate an infection.
  • The RNA displays diverse activities, as a messenger RNA, as a template for RNA replication and as the genome.
  • The virus‐encoded polyprotein is processed by proteases present within itself to make about 12 different mature products (plus important precursors).
  • Viral proteins are required both for viral RNA replication and virus assembly; in addition, some also modify specific cellular functions in order to block host antiviral responses.
  • Current vaccines rely on the production and then chemical inactivation of infectious virus.
  • Non‐infectious empty capsid particles can be produced, which are candidates as new, safer vaccines.

Keywords: animals; virus; vesicles; picornavirus; RNA; integrins

Figure 1. (a) Life cycle of FMDV within a single cell. The virus attaches to a receptor (e.g. the integrin αvβ6) on the cell surface. It is internalised within a clathrin‐coated vesicle (CCV) that fuses with an early endosome, within which the environment is relatively acidic (elevated [H+]). These conditions result in capsid disassembly; the viral ribonucleic acid (vRNA) is released and delivered (by an unknown mechanism) to the cell cytoplasm where viral protein synthesis, RNA replication and particle assembly occur before cell lysis and virus release. (b) Synthesis of foot‐and‐mouth disease virus proteins. The virion RNA, which also serves as messenger, is represented by the upper line; the proteins encoded are shown by the boxes beneath. RNA: The 8.5 kb genome is linked at its 5′ end to a viral protein, VPg (orange circle), also called protein 3B. Cn denotes poly(C), An, the poly(A) tail. The internal ribosome entry site (IRES) directs protein synthesis to be initiated at either of the arrowed positions to produce two forms of the leader (L) protease termed Lab and Lb; these mark the start of the long continuous coding region that occupies nearly all the remainder of the genome. Proteins: The viral proteins are made initially as one long polypeptide (‘polyprotein’). This contains proteases (L, 2A and 3C; filled boxes) that cleave at specific sites (↑) to generate the complete repertoire of viral proteins; P1–2A, P2 and P3 are intermediates in this process. Other functions: Viral proteins VP1, VP2, VP3 and VP4 (also called 1D, 1B, 1C and 1A, respectively) make up the protein coat, or ‘capsid’, of the virus (orange triangle is a myristic acid residue linked to the N‐terminus of VP4). VPg is encoded in three related forms. Protein 3D is the RNA polymerase that replicates the genome. The protease Lab/Lb also acts as an inhibitor of host protein synthesis.
Figure 2. Structure of foot‐and‐mouth disease virus. The capsid is built from four viral structural proteins, VP1–4. (a) A mature protomer, the smallest repeating unit, containing one copy of each of VP1–3; blue, VP1; green, VP2; yellow, VP3. Side‐chains of amino acids that are targeted by neutralising antibodies are shown in white on the peptide backbone of the protomer. Upper image is viewed from above; lower image is viewed through the plane of the capsid. (b) The capsid. Five protomers (triangle = one protomer) assemble into a saucer‐shaped, pentagonal disc, with VP1 in the centre. Twelve of these pentamers make a complete capsid. VP4 is not shown as it is entirely internal within the capsid.
Figure 3. (a) The foot of a steer with foot‐and‐mouth disease showing a fluid‐filled vesicle between the hoofs just below and to the left of the end of the forceps. (b) Erosions of the mouth resulting from the rupture of vesicles.
Figure 4. Graph to demonstrate time course of clinical signs, virus isolation and antibody production after acute infection, following contact infection, of cattle with FMDV. The graph is a pictorial representation of data accumulated from a number of cattle challenge experiments. Cattle usually start showing clinical signs of FMDV within 2–3 days after contact with infected animals; this is depicted as clinical lesions (black line) that include the severity of lesions on the mouth and feet and temperature. Generally, animals are debilitated for only 4–5 days, when they have a high temperature and newly formed vesicles. Animals with healing lesions, usually from day 7 onwards, are more inclined to eat and move normally unless there are secondary infections of the lesions. Viraemia (virus in blood, red line) is detectable soon after challenge and is maintained for approximately 7 days. Virus is also detectable in the pharynx, when samples are taken with a probang cup, soon after challenge, but in carrier animals, virus may be detectable in this site for many months after challenge without associated lesions or clinical signs (brown line). A specific antibody response to the virus is usually rapidly induced and detectable within the first week after challenge (blue line). Details: FMD virus in blood – The quantity of virus detectable in blood measured as plaque forming units (pfu) per millilitre of blood, typical peak values 107–108 pfu/mL. Clinical lesions – A score based on the severity of lesions on the feet and mouth, general demeanour and rectal temperature. FMD virus at mucosal sites – The quantity of virus detectable in probang samples measured as pfu per millilitre of pharyngeal/oesophageal fluid, typical peak values 107–108 pfu/ml. Antibody – Anti‐FMDV‐specific antibodies, usually measured as the neutralising antibody titre, are induced at about 7 days after challenge. Transmission – Studies have shown that cattle become infectious at the onset of clinical signs and are only infectious for approximately 2 days. The presence of virus or viral genome before the onset of infectiousness provides an opportunity to detect infected cattle before they transmit infection (←→).


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Further Reading

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Woolhouse MEJ (2004) Mathematical models of the epidemiology and control of foot‐and‐mouth disease. In: Domingo E and Sobrino F, (eds). Foot‐and‐Mouth Disease: Current Perspectives, pp. 355–381. Norwich, UK: Horizon Press.

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Belsham, Graham J, Charleston, Bryan, Jackson, Terry, and Paton, David J(Feb 2015) Foot‐and‐Mouth Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001024.pub3]