Abstract
The history of foot-and-mouth disease falls into several distinct areas. 1) Loeffler and Frosch's landmark description in 1897 that the disease is caused by a filterable agent, the first observation that an animal disease could be caused by a virus. 2) The search for experimental laboratory animals, culminating in the demonstration by Waldmann and Pape of the susceptibility of the guinea pig in 1920 and the suckling mouse by Skinner in 1951. 3) The discovery of three distinct serotypes O, A and C in the 1920s by Vallee and Carre in France and by Waldmann in Germany, and the subsequent recognition in the 1940s and 1950s by the Pirbright group of the three Southern African Territory Types SAT 1-3, and Asia 1. 4) The development of in vitro techniques for the growth of the virus which have been crucial for the large-scale production of vaccines and for the accurate assay of virus infectivity. Work by Hecke and the Maitlands in the early 1930s, followed by the crucial demonstration by Frenkel in 1947 that large amounts of the virus could be produced in surviving tongue epithelium, formed the basis for the vaccination programmes initiated in Europe in the 1950s. The subsequent development of cell lines has brought a remarkable degree of sophistication to the study of virus growth. 5) The impact of molecular studies on the structure of the virus and its mode of replication which have led to practical applications such as an in vitro test for vaccine potency, rapid diagnosis methods, and international epidemiological surveys. In addition, they have provided the means to design molecular vaccines.

Abstract
Foot-and-mouth disease virus (FMDV) is a member of the picornavirus family. The virus has a positive-sense RNA genome that functions like a mRNA and encodes a viral polyprotein. This polyprotein is co-translationally processed, largely by virus encoded proteases, to produce about 15 mature proteins plus many different precursors. These proteins have functions in RNA replication, modification of the host cell and in the assembly of new virus particles. The RNA genome also has to act as the template for RNA replication. This process occurs in two main stages. Initially synthesis of negative strands occurs using the positive strand template and then the production of many positive-sense infectious RNAs is achieved from the negative strands. Some of these infectious RNAs are then packaged by the structural proteins to produce new virus particles. Particular emphasis in this review is placed on the mechanism of protein synthesis initiation on the viral RNA. Early on in FMDV-infected cells, the synthesis of host cell proteins is inhibited, as a result of modifications to the cellular translation machinery that are induced by virus-encoded proteases. However, viral protein synthesis is maintained under these conditions. Initiation of protein synthesis occurs at two different start sites and is directed by a large RNA element of about 450 nt termed the internal ribosome entry site (IRES).

Abstract
Foot-and-mouth disease virus encodes all of it's proteins in the form of a polyprotein. The full-length translation product (some 2,330 amino acids) is not observed within infected cells, however, due to processing of the polyprotein. The polyprotein undergoes three co-translational, intramolecular, or 'primary', cleavages mediated by the virus-encoded proteinases L and 3C, and a short oligopeptide sequence (2A). 2A-mediated 'cleavage' is now thought to be a translational effect: an unusual ribosome 'skipping' activity. The polyprotein primary cleavage products then undergo 'secondary'proteolytic processing by a combination of inter- and intramolecular cleavages to produce the mature processing products. The aphthoviruses are unique in possessing a proteinase (Lpro) at the N-terminus of the polyprotein. The L and 3C proteinases serve not only to cleave the virus polyprotein, but to degrade certain host-cell proteins thereby greatly enhancing virus replication. The strategy of encoding proteins as polyproteins comprising virus-encoded proteinases lies, therefore, at the core of the replication strategy of these viruses.

Abstract
X-ray structures, at almost atomic resolution, of Foot-and-Mouth-Disease Virus (FMDV) particles from several serotypes and subtypes are now available mainly from the results obtained by the Oxford group during about the last 15 years. FMDVs show many of the structural features generally found in picornaviruses with virions forming icosahedral shells composed of 60 copies each of four structural proteins VP1-VP4. The disposition of the three larger proteins, VP1-VP3, follows a pseudo T=3 architecture (P=3) closely related to the one first found in small, RNA, plant viruses. The arrangement is possible by the similar topology of VP1, VP2 and VP3, which adopt the wedge-shaped eight-stranded b-barrel fold characteristic of most RNA viruses. The chain length and conformation of VP4 is quite variable among picornaviruses, though the protein is always internal and has an N-terminal myristoyl group that in the FMDV structures remains undefined. Despite the important features in common with picornaviruses FMDV presents some major differences that can often be related to functional or biological peculiarities. In particular, the canyon or pit found in most picornaviruses is absent in aphthoviruses, which place the integrin cell attachment site containing the Arg-Gly-Asp (RGD) motif in the protruding, fully exposed and highly immunogenic GH loop from VP1, also called the "FMDV loop". Some flexibility seems required for the optimal biological functioning of this loop that has always been found disordered in the crystal structures of the unperturbed virions. However, the structure of the loop has been trapped both in crystals of reduced virions from the O serotype and in crystals of peptide complexes with neutralizing antibodies against the C serotype. The self-contained structure of the "FMDV loop" together with its hinge flexibility and with the recent availability of the structure of the ectodomain from integrin avb3 suggest mechanisms for cell receptor-virus recognition and specificity.

Abstract
Effective surveillance to prevent the entry of animals with foot-and-mouth disease (FMD) into countries or areas free of the disease and to rapidly identify cases during outbreaks requires that those involved with susceptible livestock species are familiar with the clinical signs of the disease. In particular this includes state and private veterinarians, livestock owners and those responsible for animals at markets, abattoirs and agricultural shows etc. In this chapter the characteristic signs of FMD in different livestock species are described and illustrated with accompanying photographs.

Abstract

The clinical signs of foot-and-mouth disease (FMD) in cattle and pigs are those of an acute febrile vesicular illness. Persistent infection with FMDV (the carrier state) is considered to be a common sequel to both clinical and subclinical FMD in ruminants only, and is asymptomatic. Various factors influence the development and duration of persistent FMDV infection, including the genetics of the host and the viral challenge itself. The fear of FMDV carriers has led to restricted international trade in seropositive live ruminants. The mechanism employed by the virus to persist and evade immune elimination from the host is unknown. Despite the chronic stimulation of local IgA, the virus appears to persist in the epithelium of the soft palate and oropharynx. Evidence from in vitro work on persistently infected cell culture suggests a co-evolution of virus and cells, similar to some other picornavirus persistent infections. Thus despite an apparent antigenic stability of FMDV during persistence in vivo, it is possible that a tissue-specific variant is selected which can survive in a specific location without elimination. Whether this persisting virus represents a real source of infectious FMDV with the potential to cause patent disease in susceptible contact animals remains a mystery.

Abstract
Since foot-and-mouth disease virus (FMDV) was discovered to be the etiologic agent of foot-and-mouth disease (FMD) over 100 years ago, research has been directed at understanding the biology of the virus so as to be able to control this devastating disease of livestock. We have developed much knowledge over the last 30-40 years on how the virus replicates, its basic structure, and the structure of its proteins and nucleic acid. Yet, even though FMD has been controlled in developed countries through the widespread use of an inactivated virus vaccine, the inability to effectively control the virus in developing countries threatens worldwide livestock and related industries, in addition to its affect on broader economies. New technologies have now afforded us the means to control this disease both with new generation vaccines and antiviral therapies. In order to take advantage of the latter approach, detailed molecular knowledge of both host and viral factors which control the virulence and the host range of the virus is necessary. This article focuses on the cellular receptor for the virus which controls organ and host tropism, and on viral factors which are known to control either host range or virulence of the virus.

Abstract
Immune defence against foot-and-mouth disease virus (FMDV) has been related to the antibody-mediated compartments affording protection in both animal models and natural hosts. Induction of the specific immune response involves the B lymphocytes recognising epitopes on the virus particle to produce specific antibody. In addition, the concomitant recognition of T lymphocyte epitopes following antigen processing and presentation in the context of MHC class II molecules is essential. This ensures stimulation of helper (Th) lymphocytes to produce the growth and differentiation factors necessary for the development of the immune response. The humoral response in sera against FMDV is well documented, with high titres of virus-specific antibody being related to protection against challenge infection. This relationship is not absolute, because animals with the same titre of specific antibody can differ in their resistance to FMDV infection. Effector immunity involves antibody concentrations, antibody affinities, and the involvement of the phagocytic system to remove the antibody/virus complexes and destroy the virus Conversely, little is known about the role of cytotoxic lymphocytes (CTL) in protection against FMDV.

In this chapter on the immunology of foot-and-mouth disease, the immune response against FMDV will be dealt with in detail, from the induction of the response to the effector defences generated. The induction will be presented from the viewpoint of the immune system and the cellular interactions involved, as well as from the viewpoint of the virus in terms of the epitopes recognised by the compartments of the immune system. Effector immunity will be presented in terms of the current evidence on the functioning of both the innate and adaptive (or specific) immune defences. Therein, the capacity of FMDV to modulate immune responses, and use cells of the immune defence for transport in the host will also be described.

Abstract
The capsid of FMDV presents many neutralization epitopes that cluster in several exposed regions. One of the major antigenic sites involves the G-H loop of VP1, and two other major sites are defined by discontinuous epitopes that are structurally and functionally independent of that loop. The G-H loop appears as a mobile capsid element. In some virus strains this loop participates in discontinuous epitopes which may be disrupted by mutations in other capsid elements that stabilize alternative orientations of the G-H loop. In other virus strains the G-H loop delineates true continuous epitopes that can be faithfully mimicked by synthetic peptides with native-like conformational propensities, and that have been structurally and functionally characterized in detail. Some residues within this loop have a dual function in the interaction with the cell receptor and in direct recognition by many antibodies. Some of these neutralize infectivity through monovalent binding and steric inhibition of the interaction with the cell receptor. The cell attachment site of FMDV is not hidden from antibody attack, but it is protected from variation by the effect of negative selection. The extreme antigenic diversity of FMDV occur through multiple mutations, including a few critical ones, on the restricted subset of residues in each antigenic region that are involved in antibody binding, but that are not involved in other capsid functions.

Abstract
Foot-and-mouth disease virus (FMDV), as other RNA viruses characterized to date, exists and replicates as complex and dynamic mixtures of related mutants termed viral quasispecies. In this chapter we review the conceptual origins of quasispecies, and the molecular basis and biological implications of quasispecies dynamics, as viewed through FMDV. Topics covered include genetic and antigenic heterogeneity of FMDV populations, evolution of host cell recognition, molecular epidemiology of FMDV, comparative rates of evolution of FMDV and other viruses in nature, and the mechanisms operating to maintain virus identity despite high mutation rates. Considering FMDV as a complex adaptive system, we address memory in FMDV quasispecies, the consequences of Muller's ratchet, and virus entry into error catastrophe as a new antiviral strategy. Although the chapter reviews mainly experimental results, some connections with theoretical concepts are also addressed.

Abstract
he historical background of FMD vaccine production, the Valléé-Schmidt-Waldmann concept, the production of antigen in bovine tongue epithelium (Frenkel culture) and improvements achieved through the use of monolayer and suspension cultures of cell lines are described. Key elements of modern vaccine production are discussed such as the production environment, bio-safety concepts, rules for good manufacturing practice, requirements for culture medium, cells, virus strains, inactivation of viral antigen, and successive concentration and purification of the antigen. Storage of the concentrated antigen at ultra-low temperatures creates greater flexibility for the producer. In addition, it allows national and international organisations, the opportunity to establish vaccine banks for emergency vaccination. For the latter purpose it is even more important that antigens are purified. The purification of FMD viral antigens - including the removal of non-structural proteins (NSP) - provides a system that can distinguish between the immune responses of vaccinated animals from those of animals infected with live FMD virus. Consequently, the combined use of purified vaccine and anti-NSP tests essentially provides a "marker" system.

Possibilities for the world-wide control and eradication of FMD by vaccination - including the institution of regional vaccine banks - are discussed. Modern (qualified) FMD vaccines perform very well both for regular vaccination programs and for the control of outbreaks, and over the past 15 years there are no well-documented cases where cattle vaccinated with an approved vaccine have caused new outbreaks. Therefore, whether there continues to be justification for sanctions on trade, when controlling single (limited) outbreaks by (ring-) vaccination.

Abstract
Early studies with foot-and-mouth disease virus (FMDV) showed that an important antigenic site on the particle, subsequently termed antigenic site 1, is highly sensitive to proteolytic enzymes. Only VP1 is cleaved, showing that the site is present on this protein. Finally, a combination of approaches led to the location of the site within VP1. The sequence of the site is variable both in length and composition, as might be expected for an important antigenic determinant and synthetic versions of this sequence were found to elicit reasonable levels of neutralising and protective antibodies in laboratory animals, encouraging attempts to develop synthetic vaccines. Unfortunately, for reasons that are not clear, the synthetic vaccines did not perform as well in target species. Resolution of the crystal structure of FMDV showed that antigenic site 1 lies within a highly mobile loop, the G-H loop, at the surface of the virus particle and this characteristic probably accounts for its efficacy as a synthetic immunogen. In addition, the G-H loop has been shown to be the receptor binding feature of the virus. It includes a highly conserved triplet, arginine-glycine-aspartic acid, which is key to the recognition of integrin receptors on the surface of susceptible cells.

Abstract
This review considers how epidemiological models are constructed, how they deal with real-life complexities such as spatial heterogeneity, how they can be applied to specific FMD outbreaks or epidemics, and how they can be used to explore the impact of control measures. A detailed description is provided of the application of a particular model, the 'Keeling' model, of the spread of FMD between farms in the UK during the 2001 epidemic. The review concludes with a brief discussion of how mathematical modelling of livestock disease is likely to develop in the future. The emphasis throughout is on 'good practice', especially how theoretical models relate to biological data and how models can sensibly be used to inform decisions about disease control strategies.

Abstract
Among wildlife the African buffalo seems to be the only long-term maintenance host of FMD virus but, as far as is known, this is confined to SAT-type viruses. Why other types of FMD virus are apparently not maintained by buffalo remains to be explained. It is clear furthermore that buffalo transmit SAT viruses, albeit rarely, to other susceptible species with which they come in contact but the mechanisms whereby this occurs remain to be fully elucidated. The fact that buffalo do this presents a fundamental quandary for development and intensification of livestock farming in sub-Saharan Africa, especially where export of livestock and their products is the objective. This makes livestock development within integrated pastoral/wildlife systems problematic.

Controlling FMD by vaccination of wildlife in sub-Saharan Africa is not feasible because of the logistical problems of vaccinating large numbers of free-ranging animals. Furthermore, FMD vaccines appear to be less effective in some wildlife species than in livestock and, as has been shown in livestock, currently available FMD vaccines do not necessarily protect against infection as opposed to disease. Available inactivated vaccines also only provide transient immunity and need to be administered repeatedly to maintain high levels of herd immunity.

The use of fencing to separate wildlife potentially infected with FMD virus from livestock has been used successfully in southern Africa to prevent outbreaks in the latter and the possible extension of this approach to other regions of sub-Saharan Africa is a subject of debate. It is strongly opposed by the environmental lobby but, on the other hand, unless ways of profiting from the large livestock populations of the arid and semi-arid regions of sub-Saharan Africa can be found, the human populations of those regions will be consigned to continuing poverty for the foreseeable future.

Abstract
The recent outbreaks of foot-and-mouth disease in Europe have been a stimulus to bring to the market new diagnostic tests which can be used on the farm or in the laboratory to increase the speed with which suspect outbreaks can be confirmed. A more rapid diagnosis, particularly in species such as sheep that often show only mild clinical signs, would likely reduce the number of animals slaughtered during an outbreak, and allow a more accurate definition of the size and distribution of an outbreak. However, before these new tests are introduced, they must be rigorously tested under different conditions to clearly document their sensitivity and specificity, as, if they are to supplement or replace existing methods, they must provide advantages to a disease control program. The large scale slaughter that took place in the United Kingdom during the outbreak horrified the general public, and has prompted the political leaders to insist on a re-assessment of the use of vaccination as an alternative strategy. But political will is not sufficient to overcome all the problems associated with the use of vaccine in the face of an outbreak of FMD.

Abstract
Foot and mouth disease (FMD) is one of the most contagious diseases of mammals and can cause severe economic loss. The Food and Agriculture Organization of the United Nations, Office Internatioal des Epizooties and Pan-American Health Organization have had extensive programmes for FMD surveillance and control. The efforts of these organizations focus on disease reporting, disease status evaluation, safety of world trade, diagnosis and research, standardisation of FMD vaccine production, coordinated control of outbreaks (eg: in Europe in the 90's) and international support of national and regional FMD control programmes. The coordinated activities of these organizations have contributed greatly to eradication or control of FMD in many countries, and have facilitated global trade while minimising the risk of the introduction of the virus from infected to disease free zones.

Abstract
Foot- and-mouth disease (FMD) is endemic in many countries of the world, but a number of countries have attained FMD-free status, which provides economic benefits from international trade in animals and animal products. In recent years there have been serious outbreaks of FMD in countries formerly free of the disease. This chapter summarizes the world situation and addresses the question of whether resurgences of FMD fall into a general pattern of emerging and re-emerging diseases consequent upon four interlinked domains of the determinants of the emergence of infection as defined by the 2003 Institute of Medicine Report on Microbial Threats to Health: genetic and biological factors; physical environmental factors; ecological factors; and social, economic and political factors.

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