Caister Academic Press

Foot-and-Mouth Disease Virus: Current Research and Emerging Trends

"important comprehensive review reference" (JAVMA)
Publisher: Caister Academic Press
Edited by: Francisco Sobrino and Esteban Domingo
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
Pages: xii + 432
Publication date: January 2017
ISBN: 978-1-910190-51-7
Price: GB £199 or US $398Buy book or Buy online
Publication date: January 2017
ISBN: 978-1-910190-52-4
Price: US $398Buy ebook

Fifteen years after the devastating 2001 European foot-and-mouth disease (FMD) outbreak, the virus causing that shocking episode continues to pose a major threat to animal health worldwide. The development of more effective, sustainable and socially acceptable disease control measures remains a key task.

This volume provides essential scientific background on FMD and its etiological agent, FMD virus, as well as comprehensive, interdisciplinary and up-to-date information on basic research findings and applied developments contributing to FMD control. The eighteen chapters have been written by leading FMD researchers. Topics include genome organization, translation and replication, virus-coded proteinases, structure of virus particles, cell receptors and host range, the RNA polymerase, quasispecies dynamics and virus evolution, innate and acquired immune responses, and the clinical signs of FMD and its natural habitats. Further chapters deal with various aspects of disease control such as diagnosis, current and new vaccines, antivirals and models of epidemiology. The role of international organizations in FMD control and the impact of FMDV as a re-emergent virus are also addressed.

The book is required reading for everyone involved in FMD and is an important acquisition for all microbiology libraries.


"a wealth of knowledge and research from recent and historical timeframes is merged together in 18 chapters for easy reference ... this book stand(s) out from other textbooks ... I recommend this book as an important comprehensive review reference for anyone involved in FMDV research, control, and outbreak planning." from JAVMA

Table of contents
1. Introduction: Foot-and-mouth Disease: Much Progress But Still a Lot to Learn
David J. Rowlands
Pages: 1-12.
Several massive outbreaks of foot-and-mouth disease (FMD) around the turn of the century, and in particular the 2001 outbreak in the UK, provided the incentive for assembling and publishing the first edition of 'Foot-and-Mouth Disease: Current Perspectives' in 2004. It is now more than a decade since the first edition was published and the editors deemed that it is appropriate to publish this second edition which summarises some of the advances in control and prevention of the disease and in fundamental understanding of virus replication that have occurred during that time. Much progress has been made, as evidenced in the following chapters, but FMD remains as one of the most important threats to the agriculture industry and more needs to be done. Similarly, our fundamental understanding of the structure and function of the virus and its genome has advanced significantly but there remain a number of intriguing unanswered questions, many of which appear to be specific to this fascinating virus.
2. Genome Organisation, Translation and Replication of Foot-and-mouth Disease Virus RNA
Encarnacion Martinez-Salas and Graham J. Belsham
Pages: 13-42.
Foot-and-mouth disease virus (FMDV), a picornavirus, has a positive-sense RNA genome that encodes a large polyprotein. The intact polyprotein is never observed; it is co- and post-translationally processed, largely by virus-encoded proteases, to produce 15 different mature proteins plus a variety of precursors. The RNA genome also has to act as the template for RNA replication. This process occurs in two 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. The infectious RNAs are then packaged by the capsid proteins to produce new virus particles. Particular emphasis in this review is placed on the role of distinct RNA structures within the viral genome in the initiation of protein synthesis and in the initiation of RNA replication. Early on in FMDV-infected cells, the synthesis of host cell proteins is inhibited, due to modification of the cellular translation machinery that is induced by a virus-encoded protease. However, viral protein synthesis is maintained under these conditions. Replication of the viral RNA is achieved by the virus encoded RNA-dependent RNA polymerase within replication complexes assembled within the cytoplasm of the cell. Thus both viral RNA and viral protein production are dependent on the functions of virus-encoded proteins and conserved RNA structures.
3. Foot-and-mouth Disease Virus Proteinases and Polyprotein Processing
Fiona Tulloch, Garry A. Luke and Martin D. Ryan
Pages: 43-60.
Foot-and-mouth disease virus encodes all of its proteins in a single, long, open reading frame which encodes a polyprotein. The full-length translation product (~ 2,330 amino acids) is not observed within infected cells, however, due to 'processing' of this polyprotein. The polyprotein undergoes extremely rapid co-translational, intramolecular, or 'primary', cleavages at three sites by the activities of the virus-encoded proteinases L and 3C, and a short oligopeptide sequence (2A) which mediates a ribosome 'skipping' activity - a translational 'recoding' event. The primary cleavage products then undergo 'secondary' proteolytic processing by a combination of inter- and intramolecular cleavages to produce the mature processing products. The L and 3C proteinases serve not only to cleave the virus polyprotein, but also to degrade specific host-cell proteins thereby greatly enhancing virus replication and suppressing the innate immune response to infection.
4. The Foot-and-mouth Disease Virion: Structure and Function
Mauricio G. Mateu
Pages: 61-106.
X-ray crystallography, cryoelectron microscopy, nuclear magnetic resonance spectroscopy or a combination of methods have been used to determine the structure of foot-and-mouth disease virus (FMDV) virions, capsids and capsid components, and their complexes with receptors or antibodies. Interpretation and comparison of the structures solved, together with the results of many structure-based biophysical, biochemical and biological studies on the properties and functions of FMDV virions and their components, have greatly increased our understanding of FMDV biology in atomic detail. This knowledge is also facilitating the development of better anti-FMD vaccines, and may help the design of anti-FMDV drugs. The present chapter reviews the structure of the FMDV virion and many structural aspects related with different steps of the infectious cycle in which the virion participates: morphogenesis, maintenance of physical integrity, interaction with antibodies and escape from antibody recognition, recognition of cellular receptors, and viral genome uncoating. The production of FMDV empty capsids and the structure-based engineering of FMDV virions and empty capsids for the development of improved or novel anti-FMD vaccines are also reviewed.
5. Foot-and-mouth Disease Virus Receptors: Multiples Gateways to Initiate Infection
Paul Lawrence and Elizabeth Rieder
Pages: 107-136.
Since its discovery over 100 years ago as the causative agent of foot-and-mouth disease (FMD), research has been directed at understanding the biology of the foot-and-mouth disease virus (FMDV) so as to be able to control this devastating and highly contagious disease of cloven-hoofed livestock. Given its persistence and high rate of transmission, FMDV threatens worldwide livestock and related industries and has the potential for significant negative impacts on broader economies. A considerable amount of knowledge has been amassed in the last several decades on FMDV replication, structural biology, and the functionality of its RNA genome and encoded proteins. As a result, new technologies have now afforded the means to control this disease both with new generation vaccines and antiviral therapies. Despite these advances, many of the molecular features of the FMDV genome that determine virulence remain unclear. Developing detailed molecular knowledge of virus-host interactions and identifying mechanisms that might influence pathogenesis and host range will be essential to more effectively countermeasure FMD in the future. This chapter focuses on the cellular receptor molecules that have been identified for FMDV that affect organ and host tropism, as well as the non-receptor proteins and viral factors known to influence either host range or virulence of the virus.
6. The RNA-dependent RNA Polymerase 3D: Structure and Fidelity
Cristina Ferrer-Orta and Nuria Verdaguer
Pages: 137-146.
RNA viruses typically encode their own RNA-dependent RNA polymerase (RdRP) to ensure genome replication within the infected cell. RdRP function is critical not only for the virus life cycle but also for its adaptive potential. The combination of low fidelity of replication and the absence of proofreading and excision activities within the RdRPs result in high mutation frequencies that allow these viruses for a rapid adaptation to changing environments. In this chapter, we summarize the current knowledge about structural and functional aspects on RdRP catalytic complexes, focused in the FMDV polymerase 3D. The RdRP 3D also catalyzes the covalent linkage of UMP to a tyrosine on the small protein VPg. Uridylylated VPg then serves as a protein primer for the initiation of RNA synthesis. Different crystal structures of FMDV 3D catalytic complexes enhanced our understanding of template and primer recognition, VPg uridylylation and rNTP binding and catalysis. Such structural information is providing new insights into the fidelity of RNA replication, and for the design of antiviral compounds.
7. Quasispecies Dynamics Taught by Natural and Experimental Evolution of Foot-and-mouth Disease Virus
Esteban Domingo, Ignacio de la Higuera, Elena Moreno, Ana I. de Ávila, Rubén Agudo, Armando Arias and Celia Perales
Pages: 147-170.
Foot-and-mouth disease virus (FMDV) exhibits high mutation rates and replicates as complex and dynamic mixtures of related mutants termed viral quasispecies. Here we review the basics of quasispecies theory, how FMDV helped to establish a link between theory and experimental observations, and some biological implications of quasispecies for the biology of FMDV. Topics covered include the relationship between genetic and antigenic heterogeneity, the escape strategy for long-term survival, memory in viral quasispecies, consequences of bottleneck events, evolution of host cell recognition, epidemiological fitness, evidence against the molecular clock hypothesis in virus evolution, internal interactions within mutant spectra, new antiviral strategies based on the error threshold concept, and a salient evolutionary transition towards genome segmentation when FMDV was subjected to many serial passages at high multiplicity of infection. The chapter illustrates that FMDV has been an excellent model system to unveil the potential of genetically variable viruses to find molecular pathways for survival under adverse environmental conditions.
8. Clinical Signs and Pathology of Foot-and-mouth Disease
Charles Nfon, Oliver Lung, Carissa Embury-Hyatt and Soren Alexandersen
Pages: 171-178.
Foot-and-mouth disease (FMD) affects a wide range of cloven-hoofed animals and the clinical signs can be varied depending on the age, species, breed and husbandry of the affected animals and on the FMD virus strain. FMD control is highly reliant on early detection. Thus, it is crucial for front line staff and farmers to be able to recognise the obvious and subtle clinical signs and pathology of FMD, and collect the appropriate samples for confirmatory laboratory testing. This chapter describes the spectrum of clinical signs and pathology associated with FMD in different animal species.
9. Natural Habitats in which Foot-and-mouth Disease Viruses are Maintained
Wilna Vosloo and Gavin R. Thomson
Pages: 179-210.
Although many wildlife species have been shown to be susceptible to natural infection with foot-and-mouth disease (FMD) virus, only African buffalo can maintain infection with the SAT serotypes for long periods of time, making them the key wildlife species in the epidemiology of FMD in sub-Saharan Africa. There is clear evidence that the Eurasian serotypes cannot be maintained for extended periods of time by any wildlife species, including African buffalo. However, other wildlife species can transmit FMD viruses while actively infected and so act as transient sources of infection. Outbreaks of SAT-type FMD in cattle cause mild, slow-spreading disease that has limited direct impact on livestock, especially in extensive rangeland systems. The implication is that the direct impact of FMD on livestock producers in southern Africa is considerably less than indirect impacts. Geographic approaches to management of FMD based on creation of FMD-free zones with fenced boundaries, especially in extensive rangeland systems, inevitably result in a clash between the interests of livestock production and wildlife conservation, both vital for future healthy rural development. Alternative, non-geographic approaches to sanitary trade standardization have been advanced as a solution to this problem and recently amended international standards have begun to provide new opportunity on this basis.
10. Innate to Adaptive: Immune Defence Handling of Foot-and-mouth Disease Virus
Kenneth C. McCullough, Margarita Sáiz, and Artur Summerfield
Pages: 211-274.
Immune defence against foot-and-mouth disease virus (FMDV) has been related to antibody-mediated compartments affording protection in both animal models and natural hosts. Induction of specific immune response involves B-lymphocytes recognising epitopes on the virus particle to produce specific antibody. Concomitant recognition of T-lymphocyte epitopes following antigen processing and presentation in the context of MHC class II molecules ensures stimulation of helper (Th)-lymphocytes to produce growth and differentiation factors necessary for development of the immune response. The critical players for inducing effective immune defences are the dendritic cells (DCs) - key controllers of immune defence development and responsiveness, providing essential antigen presentation to T-lymphocytes and antigen delivery to B-lymphocytes. Concerning vaccination, adjuvants inducing cytokines and chemokines will regulate trafficking and function of both DCs and local lymphocytes. Inducing high titres of virus-specific antibody can relate to protection against challenge infection, although this relationship is not absolute - animals displaying similar titres of specific antibody differ in resistance to FMDV infection. This is due to effector immunity involving more than antibody - the phagocytic system is essential for removing antibody/virus complexes and destroying the virus. Although there is less documentation on cytotoxic Tc-lymphocytes, there is also now evidence of their role in immune defence against FMDV. In this chapter, the interaction of FMDV with DCs and macrophages (MΦ) - in terms of DC handling the virus for stimulating T- and B-lymphocytes and the roles of DCs and MΦ in the protective immune defence - will be discussed together with the intricacies of specific immune defence development and functionality. Induction of immune defence will be presented from the viewpoint of (i) the immune system and the cellular interactions involved, and (ii) the virus in terms of the epitopes recognised by compartments of the immune system. Effector immunity will be presented in terms of current evidence on the functioning of both 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 be described. Important issues pertaining to vaccine development and efficacy will be highlighted and discussed, in terms of understanding what the immune system requires for a vaccine to be efficacious.
11. Laboratory Diagnostic Methods to Support the Surveillance and Control of Foot-and-mouth Disease
Anna Ludi, Valerie Mioulet, Nick J. Knowles and Donald P. King
Pages: 275-286.
Foot-and-mouth disease (FMD) infects cloven-hoofed livestock and is globally one of the most widespread epizootic animal diseases. FMD is difficult and expensive to control since the causative virus FMD virus (FMDV) is highly contagious and spreads rapidly through susceptible animals. FMD remains endemic and impacts upon the rural livelihoods in many countries in Africa and Asia, from where it can spread to cause sporadic outbreaks in countries that are normally free from disease, such as the recent episodes that have occurred in East Asia (South Korea and Japan) and Europe (Bulgaria). These outbreaks reinforce the concerns about how readily the disease can pass across international borders, and stimulate the development and improvement of new assays for the detection and characterisation of FMDV. Focusing on the recent revolution in molecular and sequencing technologies, this chapter reviews the range of approaches that are increasingly being employed by FMD Reference Laboratories to support national programmes and regional roadmaps for the identification, surveillance, control and eradication of FMD.
12. Quality Attributes of Current Inactivated Foot-and-mouth Disease (FMD) Vaccines and their Effects on the Success of Vaccination Programmes
Eliana N. Smitsaart and Ingrid E. Bergmann
Pages: 287-316.
Although foot-and-mouth disease vaccines were in use at least since the 40s the policy of applying vaccination as a preventive tool and to respond to incursions in free countries, known as 'vaccination to live', only recently gained acceptance. This is reflected in changes in the World Organisation for Animal Health Code, which incorporated the new category 'FMD-free country/zone where vaccination is practised' and reduced the waiting periods to recover the status when vaccination is applied during emergencies. Major contributions were the improvements in vaccine manufacturing and quality controls, including batch control by independent bodies, and their successful field application. The combined use of vaccination with serosurveys to monitor viral activity was decisive to overcome the concerns that vaccination would hide infection. The augmented recognition of vaccination strengthened the requirement for a rapid availability of effective vaccines. This chapter describes the basics of the manufacture of vaccines as well as the evolution of modern technology and the growing acceptance of the concept that 'the process is the product'. Also addressed will be the relevance of antigen purification, the criteria for selection of vaccine strains, and the increasing role of antigen and vaccine banks as part of preventive measures to face emergencies.
13. Peptide Vaccines Against Foot-and-mouth Disease
E. Blanco, D. Andreu and F. Sobrino
Pages: 317-332.
Foot-and-mouth disease virus (FMDV) has been one of the pioneering systems in the development of synthetic peptide vaccines. Protection against FMDV infection is associated with the induction of neutralizing antibodies in the host species. The presence of a continuous B cell epitope in a loop of capsid protein VP1 prompted its use in peptide constructions that elicited high levels of neutralizing antibodies in laboratory species. Nevertheless, this first generation of linear peptides conferred limited protection in natural hosts, reflecting the difficulties inherent to reproducing the immunogenicity of an entire virus by a simplified replica, such difficulties including lack of adequate T-cell epitopes to address MHC class II polymorphism, or the inefficient presentation of B cell epitopes to the immune system. In this chapter we show how these challenges can be quite successfully overcome by a new generation of peptide vaccines that integrate B- and T- cell epitopes - the former in multimeric presentation - into a single molecular platform conferring solid protection against FMDV infection.
14. Control of Foot-and-mouth Disease by Using Replication-defective Human Adenoviruses to Deliver Vaccines and Biotherapeutics
Fayna Diaz-San Segundo, Gisselle Medina, Marvin J. Grubman and Teresa de los Santos
Pages: 333-356.
Foot-and-mouth disease (FMD) is one of the most important viral-diseases that can affect livestock worldwide. Although the disease has been successfully controlled in many geographic regions, mainly due to the enforcement of surveillance and trading policies and the use of an available inactivated whole virus vaccine formulation, challenges remain as outbreaks are constantly detected in most of the developing world. With the expansion of globalization and the exponential growth of population in today's world, recent outbreaks have wreaked havoc in disease-free countries resulting in devastating economic consequences. Novel vaccination policies that could be massively produced anywhere, that could induce early protection after vaccination at a low risk and affordable cost are needed. A novel vaccine approach using a recombinant replication-defective human adenovirus type 5 (Ad5) vector has recently been developed and has been granted for the first time in the last 50 years, a provisional U.S. license for production and use in the U.S mainland in outbreak situations. The Ad5-FMD vaccine delivers only FMDV capsid and some non-structural (NS) viral coding regions required for capsid processing and improved expression. Animals vaccinated with Ad5-FMD can be readily differentiated from infected animals (DIVA) using diagnostic assays employing the NS proteins not present in the vaccine and production of this vaccine does not require expensive high-containment manufacturing facilities since it does not contain infectious FMDV. One inoculation of this Ad5-FMD subunit vaccine can induce rapid, within 7 days, and relatively long-lasting protection in swine. Similarly cattle inoculated with one dose of this recombinant vector are rapidly protected from direct and contact exposure to virulent virus. Furthermore, cattle given two doses of this vaccine developed high levels of FMDV-specific neutralizing antibodies, suggesting that the Ad5 vector approach may be useful in semiannual FMD vaccine campaigns. To stimulate protection prior to the vaccine-induced adaptive immune response we have explored the possibility of using biotherapeutics also delivered by recombinant Ad5. Delivery of type I, type II and type III interferon (IFN) can fully protect swine against challenge with multiple FMDV serotypes. Similarly, delivery of type III IFN can protect cattle against FMD. Interestingly a combined approach of Ad5-FMD vaccine and Ad5-IFN can protect animals as early as 1 day post vaccination and protection can be complete. Thus, this combination approach successfully addresses a number of concerns of FMD-free countries with the current disease control plan. By rapidly limiting virus replication and spread, this strategy may reduce the number of animals that need to be slaughtered during an outbreak as well as allow for differentiation of vaccinated from infected animals In this chapter we will review the development of these approaches and current efforts to improve the strategy to make it affordable and effective for global use.
15. Antiviral Therapies for Foot-and-mouth Disease
Annebel R. De Vleeschauwer, David J. Lefebvre and Kris De Clercq
Pages: 357-384.
Prevention and control of foot-and mouth disease (FMD) is traditionally based on zoo-sanitary measures and vaccination. The genetic and antigenic diversity of the FMD virus (FMDV), its highly infectious nature and enormous dynamic potential illustrate that pan-serotype targeted control measures inhibiting viral replication immediately upon administration would be a valuable support tool or alternative to vaccination to smother FMD outbreaks in an early stage. In this respect, antiviral drugs against FMDV come into focus. Many research groups have pursued various approaches in search of anti-FMD therapies. Although the research topic is rather young some encouraging achievements have been reported, but for all approaches several issues still need to be addressed before reliable practical application can be reached. In this chapter we review the history and the state of the art of antiviral drugs against FMDV. Nucleoside analogues, small chemical molecules, oligonucleotides, new molecular biological techniques such as RNA interference, single-domain antibodies and derivatives from natural products are covered. Overall challenges and strengths and weaknesses specific to the different approaches are discussed.
16. Mathematical Models of the Epidemiology and Control of Foot-and-mouth Disease
Michael J. Tildesley, William J.M. Probert and Mark E.J. Woolhouse
Pages: 385-408.
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 discussion of how modelling has developed since the 2001 outbreak and 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.
17. The Role of International Organizations in the Control of Foot-and-mouth Disease
Bernard Vallat, Joseph Domenech and Alejandro A. Schudel
Pages: 409-416.
During recent years and in the years to come there has been and there will be a significant increase in food production due to the intensification of the production systems, which has to respond to the increase in demand related to the need of feeding more than 9000 million people. These trends have resulted in an increase in the regional and international exchanges of live animals and animal products and due to this globalization and other factors, diseases affecting animals are playing a key role in livestock productions, affecting food security, food safety and the economy worldwide. Foot and Mouth Disease (FMD) is a highly contagious vesicular disease of cattle and other cloven-hoofed animals. Although mortality due to the disease is very low and mostly restricted to young animals, a drastic decrease in productivity and working capacity of the animals causes losses to the livestock industry. The disease has an important socio-economic impact in countries where it is endemic, provokes huge economic consequences when outbreaks occur in disease free regions, and is considered one of the most important constraints to international trade of livestock and animal products. To effectively control FMD, a trans-boundary disease by nature, and its impact on the international trade of animals and products, requires a focus that goes beyond individual countries. This is where international and regional organizations play a crucial role in effectively advancing in its control and eradication. The recent success of the program to eradicate Rinderpest from the world achieved in 2011 has been a mayor incentive in motivating international organizations and countries to embark on a similar road for the control of FMD. Controlling Trans-boundary Animal Diseases (TAD) such as FMD at the source is a shared interest between infected and uninfected countries and is considered a Global Public Good. The Office International des Epizooties/World Animal Health Organization (OIE) and the Food and Agricultural Organization (FAO) of the United Nations have been leading, under their respective areas of competence, the organization of a global response in order to face the challenge of controlling FMD worldwide. The Global FMD Control Strategy they have defined is being implemented under the OIE/FAO Global Framework for Progressive Control of Trans-boundary Animal Diseases (GF TAD) initiative, which was approved by both international organizations in 2004. As a result they have developed tools, promoted and organized regional activities and coordinated programs to control FMD worldwide as well as reducing the risk of the spread of FMD through international trade.
18. Overview of Foot-and-mouth Disease and its Impact as a Re-emergent Viral Infection
Brian W.J. Mahy and Graham J. Belsham
Pages: 417-426.
Foot-and-mouth disease (FMD) remains endemic in many countries of the world, but certain regions (e.g. Europe and North America) 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 which are normally free of the disease and the spread of certain viruses (e.g. SAT 2) outside of their normal geographical area. This chapter briefly summarizes the current 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 namely: genetic and biological factors; physical environmental factors; ecological factors; and social, economic and political factors.

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(EAN: 9781910190517 9781910190524 Subjects: [medical microbiology] [microbiology] [molecular microbiology] [virology] )