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Bovine Tuberculosis

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This book is contemporary, topical and global in its approach, and provides an essential, comprehensive treatise on bovine tuberculosis and the bacterium that causes it,ÊMycobacterium bovis. Bovine tuberculosis remains a major cause of economic loss in cattle industries worldwide, exacerbated in some countries by the presence of a substantial wildlife reservoir. It is a major zoonosis, causing human infection through consumption of unpasteurised milk or by close contact with infected animals.ÊFollowing a systematic approach, expert international authors cover epidemiology and the global situation; microbial virulence and pathogenesis; host responses to the pathogen; and diagnosis and control of the disease.ÊAimed at researchers and practising veterinarians, this book is essential for those needing comprehensive information on the pathogen and disease, and offers a summary of key information learned from human tuberculosis research. It will be useful to those studying the infection and for those responsible for controlling the disease.

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16 Chapters

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1 Bovine Tuberculosis: Worldwide Picture



Bovine Tuberculosis:

Worldwide Picture

Lina Awada, Paolo Tizzani, Elisabeth Erlacher-Vindel,

Simona Forcella and Paula Caceres*

World Organisation for Animal Health (OIE), Paris, France

1.1 Introduction

Bovine tuberculosis caused by Mycobacterium bovis is a disease of livestock and wildlife and causes global economic losses, including those resulting from trade barriers (OIE, 2015), estimated at several billion USD annually despite widespread control efforts (Schiller et al., 2010).

The objective of this chapter is to provide information on the worldwide bovine tuberculosis situation, using data from the OIE. The OIE’s

World Animal Health Information System

(WAHIS), is a reference for conducting global analyses in this field.

1.1.1  The World Organisation for

Animal Health and the World Health

Information System

The dissemination of rinderpest in Europe in

1920, resulting from a shipment of infected zebu cattle originating from India and destined for Brazil transiting through the Belgium port of


2 Mycobacterium bovis as the Causal Agent of Human Tuberculosis: Public Health Implications



Mycobacterium bovis as the

Causal Agent of Human Tuberculosis:

Public Health Implications

Francisco Olea-Popelka,1,* Anna S. Dean,2 Adrian Muwonge,3

Alejandro Perera,4 Mario Raviglione2 and Paula I. Fujiwara5


of Veterinary Medicine and Biomedical Sciences, Department of Clinical Sciences and Mycobacteria Research Laboratories, Colorado

State University, Fort Collins, USA; 2Global TB Programme, World Health

Organization, Geneva, Switzerland; 3Genetics and Genomics, Roslin Institute,

Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh,

UK; 4United States Embassy, Mexico City, US Department of Agriculture,

Animal and Plant Health Inspection Service, Mexico City, Mexico; 5International

Union Against Tuberculosis and Lung Disease, Paris, France

2.1 Introduction

Mycobacterium bovis, the causal agent of bovine tuberculosis (TB) can also infect and cause TB in a variety of domestic and wild animals (see


3 Economics of Bovine Tuberculosis: A One Health Issue



Economics of Bovine Tuberculosis:

A One Health Issue

Hind Yahyaoui Azami1,2,3 and Jakob Zinsstag2,3,*


Agronomique et Vétérinaire Hassan II, Rabat, Morocco; 2Swiss Tropical and

Public Health Institute, Basel, Switzerland; 3University of Basel, Basel, Switzerland

This chapter is focused on the economics of bovine tuberculosis (TB), taking into consideration the burden of this disease for livestock and also for human health, with a strong emphasis on One Health (OH) as a control approach. The current chapter starts with an overview of One

Health, followed by a review of the economics of bovine TB as an OH issue, through a summary of One Health and its added value for bovine TB and human TB control.

3.1  One Health

OH can be defined as the added value of closer cooperation between human and animal health in terms of better health of humans and animals, financial savings and improved ecosystem services (Zinsstag et al., 2015). OH is part of the broader consideration of ecology and health. It contributes to improving health by engaging different institutions and disciplines in a closer way by improved communication, closer collaboration and better information sharing based on the recognition that human and animal health are mutually dependent.


4 The Epidemiology of Mycobacterium bovis Infection in Cattle



The Epidemiology of Mycobacterium bovis Infection in Cattle

Andrew J.K. Conlan* and James L.N. Wood

Disease Dynamics Unit, Department of Veterinary Medicine, University of

Cambridge, Cambridge, UK

The epidemiology of bovine tuberculosis is, by its very nature, inconsistent. Mycobacterium bovis is poorly transmissible between cattle, but has a high potential for spread due to the chronic nature of infection. The risk of infection, susceptibility and progression of disease in individual animals is highly variable but it does vary systematically with age (Brooks-Pollock et al.,

2013; Downs et al., 2016), breed (Ameni et al.,

2007), host genetics (Allen et al., 2010;

­Bermingham et al., 2014) and production type

(Broughan et al., 2016), which in themselves will vary in different epidemiological contexts.

Resolving the impact of these biological factors on transmission is difficult as transmission rates, the duration of latency and the immunological response of infected animals to diagnostic tests all compete on timescales comparable to the life expectancy of the host. As a consequence, despite rich detailed surveillance data and a


5 Mycobacterium bovis Molecular Typing and Surveillance



Mycobacterium bovis Molecular

Typing and Surveillance

Robin A. Skuce,1,2,* Andrew W. Byrne,1,2 Angela Lahuerta-Marin1 and Adrian Allen1


Sciences Division, Agri-Food and Biosciences Institute, Belfast, UK; of Biological Sciences, Queens University Belfast, Belfast, UK


5.1  Bovine Tuberculosis

Mycobacterium bovis is a highly ‘successful’ pathogen with a worldwide distribution (Bezos et al., 2014). In several countries, bovine tuberculosis (TB) remains a major and costly infectious disease of cattle and other domesticated, feral and wild animals (Pollock and Neill, 2002;

Mathews et al., 2006; Carslake et al., 2011). It is considered the most complex and costly multispecies endemic disease currently facing the

­government, veterinary profession and farming industry in the UK and Ireland at least (­Reynolds,

2006; Sheridan, 2011), where it impacts negatively on-farm profitability, trade and the welfare of affected farming families. It can also decimate years of livestock genetic improvement.


6 Bovine Tuberculosis in Other Domestic Species



Bovine Tuberculosis in Other

Domestic Species

Anita L. Michel*

Department Veterinary Tropical Diseases, Bovine Tuberculosis and Brucellosis

Research Programme, Faculty of Veterinary Science, University of Pretoria,

Onderstepoort, South Africa

6.1 Introduction

The ability of Mycobacterium bovis to cause

­disease in a wide range of domestic and wild mammal species classifies this pathogen among the globally most widespread infectious causes of livestock production losses across many, highly diverse animal production systems (Buhr et al., 2009; Humblet et al., 2009; Schiller et al.,

2011; Food and Agriculture Organisation,

2012). In the World Organisation for Animal

Health (OIE) Terrestrial Animal Health Code, bovine tuberculosis (TB) is currently listed within the categories of diseases of cattle and those of farmed Cervidae, which indicates a recognition by the OIE of the rising importance of

M. bovis infections in production animals other than domestic cattle in terms of global trade


7 Role of Wildlife in the Epidemiology of Mycobacterium bovis



Role of Wildlife in the Epidemiology of

Mycobacterium bovis

Naomi J. Fox,1 Paul A. Barrow2 and Michael R. Hutchings1,*


Edinburgh, UK; 2The University of Nottingham, Nottingham, UK

Although Mycobacterium bovis is classically thought of as a cattle disease, this name belies its diverse range of hosts. M. bovis has one of the widest known host ranges of any zoonotic pathogen, and has been isolated from multiple members of a majority of mammal orders, from rodents and insectivores, to primates and carnivores (O’Reilly and Daborn, 1995; Coleman and

Cooke, 2001; Delahay et al., 2002).

The presence of wildlife hosts may hinder attempts to eradicate M. bovis in livestock. However, the isolation of M. bovis from an animal population does not necessarily implicate that species as important in disease outbreaks. A host’s role in disease dynamics is dependent on a plethora of interacting factors, including the structure and location of lesions determining levels and routes of excretion, host behaviour, and likelihood of contact (direct and indirect) between infectious and susceptible individuals.


8 Molecular Virulence Mechanisms of Mycobacterium bovis



Molecular Virulence Mechanisms of

Mycobacterium bovis

Alicia Smyth and Stephen V. Gordon*

School of Veterinary Medicine, University College Dublin, Dublin, Ireland

8.1 Introduction

Infection with Mycobacterium bovis is an ongoing problem both to human and animal health, costing billions annually in economic losses

(Skuce et al., 2011; Muller et al., 2013). While eradication in some countries has met with success, infection of animals and humans with

M. bovis is still reported globally. Understanding the virulence mechanisms that allow M. bovis to survive in vivo, cause disease and transmit to new (and diverse) hosts will be key to the ultimate eradication of M. bovis infection.

M. bovis is a member of the Mycobacterium tuberculosis complex (MTBC), the grouping of genetically related mycobacterial species that cause tuberculosis in mammals (Frothingham et al., 1994; Smith et al., 2006). Theobald Smith was the first to demonstrate that the causative agent of tuberculosis in cattle, and indeed other animal hosts, was not the same as the human bacillus, a finding that ultimately led to the description of the bovine-adapted species


9 The Pathology and Pathogenesis of Mycobacterium bovis Infection



The Pathology and Pathogenesis of

Mycobacterium bovis Infection

Francisco J. Salguero*

Department of Pathology and Infectious Diseases, School of Veterinary Medicine,

University of Surrey, Guildford, UK

9.1 Introduction

Mycobacterium bovis is able to infect a wide variety of domestic and wild animals, including humans (O’Reilly and Daborn, 1995). M. bovis is a member of the Mycobacterium tuberculosis complex (MTBC), which also includes M. tuberculosis, M. bovis, M. africanum, M. microti, M. caprae, M. canetti, M. pinnipedii and M. mungi

(Rodriguez-Campos et al., 2014).

Bovine tuberculosis is the infectious disease of cattle caused by M. bovis or M. caprae

(Domingo et al., 2014). The disease follows a chronic course with the formation of a granulomatous, caseous and necrotizing inflammatory process affecting mainly the respiratory tract

(lungs and draining lymph nodes) or other locations, including the gastrointestinal tract and secondary lymphoid organs.


10 Innate Immune Response in Bovine Tuberculosis



Innate Immune Response in

Bovine Tuberculosis

Jacobo Carrisoza-Urbina,1 Xiangmei Zhou2 and

José A. Gutiérrez-Pabello1,*


de Microbiología e Inmunología, Facultad de Medicina

Veterinaria y Zootecnia, Universidad Nacional Autónoma de México,

México; 2Veterinary Pathology Department, College of Veterinary Medicine,

China Agricultural University, P. R. China

10.1 Introduction

The innate immune system is the first line of defense against pathogens, of which some of its functions include participation in activation and direction of adaptive immunity, as well as maintaining the integrity and tissue repair (Kumar et al., 2011). The innate system is integrated by macrophages, dendritic cells (DCs), neutrophils and natural killer (NK) cells. These cells use pathogen-recognition receptors (PRRs) for their activity, which are responsible for identifying the presence of conserved structures between microorganisms known as pathogen-associated molecular patterns (PAMPs); similarly, they recognize molecules from damaged cells known as damage-associated molecular patterns (DAMs).


11 Adaptive Immunity



Adaptive Immunity

Jayne Hope1,* and Dirk Werling2


Roslin Institute, University of Edinburgh, Edinburgh, UK;

2The Royal Veterinary College, Hatfield, UK

Immunity to mycobacterial infections is an interplay between innate and adaptive immune responses; both cellular and humoral mechanisms are involved. While it is clear that the response to mycobacterial infection is driven and shaped by the initial innate immune response, defining the mechanisms of adaptive immunity underpins on-going efforts to develop effective tuberculosis (TB) vaccines for humans and

­cattle. Importantly, definition of correlates of protective immunity that can be measured readily will facilitate the development and screening of vaccine candidates and assessment of their success. However, it must also be stressed that in the case of mycobacterial infection, these correlates of protective immunity must be defined carefully. They not only include an ‘absence of clinical symptoms’, a definition used for many other veterinary vaccines, but must be defined as ‘protection to infection’, given the socio-­ economic importance of infection with Mycobacterium bovis. In addition, since measurement of the adaptive immune response through tuberculin skin testing or assessment of antigenspecific IFN-g release forms the basis of currently used diagnostic tests (Waters et al 2011; Pai et al., 2014), increased knowledge of the immune response associated with infection or induced by vaccination is required for improved surveillance.


12 Immunological Diagnosis



Immunological Diagnosis

Ray Waters1,* and Martin Vordermeier2


Animal Disease Center, Agricultural Research Service, United States

Department of Agriculture, Ames, Iowa, USA; 2Tuberculosis Research Group,

Animal and Plant Health Agency, Addlestone, UK

12.1 Introduction

Bovine tuberculosis (TB) is generally considered a slowly progressive disease of extended duration (lasting years), and most cattle do not exhibit readily apparent clinical signs of infection until late in the course of disease (Waters,

2015). Currently, agent-based strategies for the detection of tuberculous cattle, such as detection of bacilli within bodily excretions, are generally unreliable for use as ante-mortem tests, possibly due to the paucibacillary nature of the disease resulting in a transient and low level of bacterial shedding (Good and Duignan, 2011).

Thus, traditional clinical and microbiological techniques are rarely used for the ante-mortem diagnosis of bovine TB. Fortunately, Mycobacterium bovis is highly immunogenic in cattle, eliciting robust cell-mediated immune (CMI)


13 Biomarkers in the Diagnosis of Mycobacterium tuberculosis Complex Infections



Biomarkers in the Diagnosis of Mycobacterium tuberculosis

Complex Infections

Sylvia I. Wanzala1 and Srinand Sreevatsan2,*


of Pathobiology and Diagnostic Investigation, Michigan State University,

East Lansing, Michigan, USA; 2Department of Veterinary Population Medicine,

College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA

13.1 Introduction

laborious multistep procedure involving the caudal fold test (CFT) and the comparative cerviBovine tuberculosis (bovine TB) is a zoonotic cal test (CCT) or g-interferon release assays. The infection in cattle caused by the intracellular current diagnostics are problematic: CFT lacks bacterium, Mycobacterium bovis that belongs to specificity for M. bovis and fails to detect all disthe Mycobacterium tuberculosis complex (MTB eased cattle, while the g-interferon assay is costly complex), a group of related mycobacteria that and requires blood samples to be processed cause TB in mammals. Bovine TB is the most within 24 hours of collection. Moreover, early prevalent infectious disease of dairy cattle detection of subclinical infection by serological worldwide (Cosivi et al., 1998), causing a con- tests is hindered, since the humoral immune servative annual loss of about US$3 billion response in bovine TB occurs at a late stage of


14 Vaccination of Domestic and Wild Animals Against Tuberculosis



Vaccination of Domestic and Wild

Animals Against Tuberculosis

Bryce M. Buddle,1,* Natalie A. Parlane,1 Mark A. Chambers2,3 and

Christian Gortázar4


Hopkirk Research Institute, Palmerston North, New Zealand; and Plant Health Agency – Weybridge, Addlestone, Surrey, UK; 3School of

Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, UK;

4SaBio – Instituto de Investigación en Recursos Cinegéticos IREC, Universidad de

Castilla-La Mancha & CSIC, Ciudad Real, Spain


14.1 Introduction

Mycobacterium bovis has a very wide host range and is the predominant cause of tuberculosis

(TB) affecting domestic and wild animals, although tuberculosis in animals can also be caused by other members of the Mycobacterium tuberculosis complex. The disease in cattle, defined as bovine TB, continues to be a major economic animal health problem worldwide

(Waters et al., 2012). The test-and-slaughter bovine TB control programmes introduced in many countries in the mid-20th century achieved dramatic results and a number of countries were able to eradicate this disease.


15 Managing Bovine Tuberculosis: Successes and Issues



Managing Bovine Tuberculosis:

Successes and Issues

Paul Livingstone1,* and Nick Hancox2


Consultant, Domestic Animals and Wildlife, New Zealand;

2OSPRI, New Zealand

15.1 Orientation

Infection with Mycobacterium bovis (TB) impacts on a wide spectrum of animals including man.

The reality of managing M. bovis, wherever it is found, is that it requires adequate resources.

These are either lacking or prioritized for other needs and wants for large sections of the world.

The World Bank has categorized countries according to four income-related classes based on their gross national income (GNI) per capita in US dollars (The World Bank, 2016a). They are: low, low–medium, medium–high and high

GNI economies. These categories provide an approach for proposing management options for bovine TB that take account of available resources. For the purpose of this chapter, countries in the low, low–medium and medium–high


16 Perspectives on Global Bovine Tuberculosis Control



Perspectives on Global Bovine

Tuberculosis Control

Francisco Olea-Popelka,1 Mark A. Chambers,2,3 Stephen Gordon4 and Paul Barrow5,*


of Clinical Sciences, College of Veterinary Medicine and Biomedical

Sciences, Colorado State University, Fort Collins, Colorado, USA; 2Animal and

Plant Health Agency – Weybridge, Addlestone, Surrey, UK; 3School of Veterinary

Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK;

4UCD School of Veterinary Medicine, University College Dublin, Dublin, Republic of Ireland; 5School of Veterinary Medicine and Science, University of Nottingham,

Sutton Bonington, Loughborough, UK

16.1 Introduction

In the preceding chapters the authors have distilled the current status of research on bovine tuberculosis (TB) and the challenges and opportunities that lie ahead on the path to disease control. In this final chapter, we present some of our own thoughts on the control of bovine TB, highlighting the relevant chapters where particular issues are dealt with in more depth. While great strides have clearly been made in our understanding of the fundamental pathogen biology of Mycobacterium bovis and its interaction with the bovine host, substantial challenges remain in diagnosis, vaccination, disease epidemiology, public health and ultimate eradication.



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