The interplay between host and pathogen genetics in the increasing incidence of bovine tuberculosis

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

Tuberculosis (TB) is an infectious, respiratory disease of humans and animals caused by several species of the Mycobacteriaceae family of bacteria. Mycobacterium bovis (M. bovis) is the bacterium that causes TB in cattle (bovine TB) and a wide range of other mammals, including wild animal species such as badgers in the UK and Ireland and possums in New Zealand. They can act as natural reservoirs of M. bovis infection, posing a major impediment to eradication of bovine TB from cattle. Bovine TB presents a barrier to local, national and international free trade with annual economic costs estimated at ~$3 billion worldwide. Bovine TB has existed in the UK and Ireland for centuries and is of growing importance to the UK rural economy. It has a complex biology, involving transmission between and within populations of cattle and populations of wildlife, and still causes a number of human infections annually. Despite sustained and costly implementation of an eradication programme since the 1950s, based on regular testing of cattle, slaughter of test positive cattle, inspection of carcases at the slaughterhouse and crippling restrictions on movements from infected herds, bovine TB has not been eradicated. An acceptable bovine TB vaccine for use in cattle or wildlife is several years away. Despite intensive research on disease detection, on new vaccine candidates and on control of wildlife populations, there has been a largely unexplained increase in TB over the last 15 years, with TB spreading to new areas. Alternative control approaches need to be considered. This proposal will test our hypothesis: the outcome of infection with TB is influenced both by the genetics of the host and the molecular subtype of the pathogen. There is compelling evidence from extensive studies in several species, including humans, mice and deer, to suggest that susceptibility to TB is influenced by the genetics of the animal and that resistance to TB can be inherited. New genetic markers and high-throughput technologies allow us to detect differences in the genetic make-up of individual animals. We initially propose to link two existing datasets, one recording pedigree data (cattle parentage and offspring), the other containing test results for individual animals. We will investigate whether calves of certain bulls are more likely to develop TB. This will provide evidence that susceptibility to TB in cattle is inherited. We will then use the database of animal, slaughterhouse and laboratory test results to select cattle that have bovine TB (cases) and identify other cattle in the same herd, of the same age etc., which should be equally exposed to TB, but are TB negative (controls) and take blood or tissue samples from >500 TB cases and >500 non-TB controls and extract DNA. A high-density panel of 10,000 cattle genetic markers will be applied to this DNA, to investigate whether variation in certain cattle genes is associated with TB cases. This will identify genetic markers associated with TB resistance. New methods to detect different subtypes of TB bacteria have been developed and we will investigate whether the subtype of TB influences the outcome of TB infection in cattle, including the TB test result. Maybe some TB strains are more difficult to detect, with current tests, than others. Potential outcomes include: 1) fundamental insight into the host genetic component to the risk of acquiring TB and the influence of pathogen strain, 2) new light on immune mechanisms which could be exploited to improve diagnosis and vaccine strategies, 3) the possibility of breeding cattle for increased TB resistance. This is a collaboration between Roslin Institute, the UK's leading research institute for animal genetics and Queen's University Belfast, which has an international reputation for research on bovine TB. It is an innovative, multidisciplinary research proposal that exploits recent scientific developments and technical advances to investigate bovine TB.

Technical Summary

Bovine tuberculosis (TB), caused by the bacterium Mycobacterium bovis, is an endemic disease of major importance to UK rural economies. It has a complex epidemiology. Alternative control strategies are needed, as despite a sustained and costly eradication scheme, and intensive research on diagnostic, vaccine and wildlife interventions, there has been a largely unexplained increase in TB incidence over the last 15 years. This proposal will test the hypothesis that resistance to, and outcome of, infection with TB is influenced by host genetics and by pathogen subtype. Compelling evidence from extensive studies in humans and animal species suggests that susceptibility to TB is influenced by host genetics. Initially, through quantitative, data-driven (existing data) analyses the proposal addresses the fundamental question: is there a significant genetic component to TB risk? Secondly, through field-based sampling we propose to collect a unique set of greater than 500 TB 'case' and greater than 500 non-TB 'control' blood/tissue samples, DNA from which will be subjected to high-density whole genome scan with greater than 10K SNPs. Associations between genetic variation/markers in the host and outcome of infection will be obtained. Candidate TB susceptibility/resistance genes will be investigated further. We propose to investigate the link between pathogen genotype and features of disease, such as test responses, using multivariable analyses. Outcomes from this project include: 1) fundamental insight into the host genetic component to risk, and the influence of pathogen strain, 2) new light on immune mechanisms (and genetic variation in immune system components) which could be exploited to improve diagnosis, vaccine strategies or understanding of resistance/susceptibility, and 3) evidence determining whether breeding for resistance is possible, along with suggested first steps in this process. Potential applications, e.g. the preferential use of sires with favourable resistance genotypes, will be explored.

Publications

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Related Projects

Project Reference Relationship Related To Start End Award Value
BB/E018335/1 01/01/2008 30/04/2008 £518,670
BB/E018335/2 Transfer BB/E018335/1 01/05/2008 31/01/2012 £485,494
 
Description Host genetics influences the likelihood that a cow will succumb to infection with Mycobacterium bovis, the causal agent of bovine tuberculosis (BTB).
Genetic markers can potentially be used to genetically select cattle that are more resistant to bTB, or avoid cattle that are more susceptible to bTB.
SNP genotyping of cases and controls identified potential regions of the genome that influence bTB resistance.
M. bovis genotypes play a role in the level of pathology seen in cattle in the field.
Developed advanced statistical models for analysing the data.
Developed a biobank of blood samples from genotyped and phenotyped cattle.
We have exceeded our original objectives.
Exploitation Route The results and outputs from this project lay the basis for selecting cattle on the basis of their genetic merit for bTB resistance.
Further funding has been secured to investigate the potential for genomic selection for bTB resistance.
Sectors Agriculture, Food and Drink

 
Description We have quantified host and pathogen factors associated with bTB risk and our findings have indicated that at least 25% of the variation in host bTB can be accounted for by genetics. We have identified chromosomal regions associated with bTB case phenotype. In contrast, we have shown that M. bovis genotype does not appear (at least in the UK) to influence the bTB skin test, nor transmissibility. However there was a significant effect of pathogen genotype on the degree of pathology. Our results indicate that they are applicable industry-wide. Constructive discussions have taken place with industry, and Egenes are planning to develop estimated breeding values for UK Holstein sires for bTB resistance. Further advancements may be possible using SNP based marker assisted (genomic) selection. Our results have been presented at several international scientific conferences, scientific papers, both nationally and internationally. Data has been lodged in open access databases. We anticipate that our data will lead to reduced susceptibility of cattle to infection with M. bovis, and this should be associated with health, welfare and productivity benefits for cattle, farmers and the dairy industry and ultimately reduce the requirement for expensive monitoring and culling of infected animals.
First Year Of Impact 2012
Sector Agriculture, Food and Drink
 
Description Animal Health Research Club (ARC)
Amount £839,502 (GBP)
Funding ID BB/L004054/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2014 
End 09/2017
 
Title TB Project Genotyping Results 
Description Raw SNP data and ancillary files from genome wide association studies on bovine tuberculosis BBSRC funded projects: CEDFAS initiative grants BB/E018386/1 and BB/E018335/1 and 2; Animal Health Research Club grant BB/L004054/1; Institute Strategic Programme Grants (ISP3 Innate Immunity & Endemic Disease) [BB/J004227/1], (ISP1 Analysis and Prediction in Complex Animal Systems) [BB/J004235/1] and (ISP2 Control of Infectious Diseases) [BB/P013740/1]. Abstract Holstein-Friesian raw SNP data. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Dataset related to publication: 5. Wilkinson, S., Bishop, S.C. Allen, A.R., McBride, S.H., Skuce, R.A., Bermingham, M., Woolliams, J.A. and Glass, E.J. (2017) Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows. BMC Genomics, 18: 477. Dataset linked to Bermingham et al, 2014, Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis. Heredity, 112, 543-551. 
URL https://www.research.ed.ac.uk/portal/en/datasets/liz-glass-tb-project-genotyping-results(7aa9bca3-a0...
 
Description Collaboration relating to genetics of bovine tuberculosis 
Organisation Agri-Food and Biosciences Institute
Country United Kingdom 
Sector Public 
PI Contribution Secured two rounds of grant funding from BBSRC. Expertise in genome wide association studies.
Collaborator Contribution Epidemiology of bovine TB and data and samples from cases and controls to genotype and analyse.
Impact Multi-disciplinary: AFBI: epidemiology; bovine TB expertise; data analysis; surveillance Roslin: genetics; GWAS; genotyping; immunogenetics; innate immunity; host-pathogen interactions Outputs: See BB/E018335/1 and BB/E018335/2; BB/L004054/1; BB/L004119/1 Publications: Bermingham ML, Handel IG, Glass EJ, Woolliams JA, de Clare Bronsvoort BM, McBride SH..Bishop SC. (2015). Hui and Walter's latent-class model extended to estimate diagnostic test properties from surveillance data: a latent model for latent data. Scientific reports, pp. 11861 Bermingham ML, Bishop SC, Woolliams JA, Pong-Wong R, Allen AR, McBride SH..Glass EJ. (2014). Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis. Heredity, 112 (5), pp. 543-51 Tsairidou, S. Woolliams, J.A., Allen, A.R., Skuce, R.A., McBride, S.H., Wright, D.M., Bermingham, M.L., Pong-Wong, R., Matika, O., McDowell, S.W., Glass, E.J., Bishop, S.C. Genomic prediction for tuberculosis resistance in dairy cattle (2014) PLoS ONE, 9, e96728. doi:10.1371 Tsairidou S, Woolliams JA, Allen AR, Skuce RA, McBride SH, Wright DM..Bishop SC. (2014). Genomic prediction for tuberculosis resistance in dairy cattle. PloS one, 9 (5), pp. e96728
Start Year 2006
 
Description BBSRC Dairy Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation in a BBSRC organised workshop to showcase BBSRC funded research of relevance to representatives of Dairy UK.
Year(s) Of Engagement Activity 2012
 
Description Bovine tuberculosis and host genetics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation and discussion by Profs Glass and Bishop with Lord John Taylor, Spokesperson for Department for Environment, Food and Rural Affairs.
Year(s) Of Engagement Activity 2012
 
Description Genetics of host resistance to bTB & engagement with industry 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Pros Bishop, Woolliams and Glass presented results of case control study and discussed potential engagement with industrial partners.
Year(s) Of Engagement Activity 2012
 
Description Genomics of bTB Cattle Practice 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation to BCVA Congress & report 2008: Minozzi, G, Bishop, SC, Skuce, RA, Allen, A, McDowell, SWJ., Woolliams, JA, Glass, EJ (2008). Genomics of Host Resistance to Bovine Tuberculosis. Cattle Practice, 16(3):238), describing the aims and background to BB/E018335/1, BB/E018335/2 & BB/E018386/1.
Year(s) Of Engagement Activity 2008
 
Description Interview for BBC Radio 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview Broadcast for BBC Radio 4 Farming Today, Radio Ulster FarmGate, Radio Wales.
Year(s) Of Engagement Activity 2011
 
Description Interview for Farmers Weekly 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Interview resulted in an article: Bovine TB resistance gene found in cattle.
Year(s) Of Engagement Activity 2011
 
Description Interview for Veterinary Times 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview for Veterinary Times with Emma Cooper: Research boosts chance of bTB-resistant cattle.
Year(s) Of Engagement Activity 2011
 
Description Interview for Yorkshire Post 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview resulted in an article in the Yorkshire Post: World on brink of cow TB breakthrough.
Year(s) Of Engagement Activity 2011
 
Description Media Brief at Stakeholder Forum 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact BBSRC CEDFAS Stakeholder Forum, October 2011, London. Media Brief. Local and national
agricultural and popular press and internet news ran this story e.g. Farmers Guardian, Farmers Weekly, Farmers Guardian, Veterinary Times, Cattle Site, Beef site, Animal Pharma etc.
Year(s) Of Engagement Activity 2011
 
Description Roslin Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact UK food and farming benefits from research to combat animal diseases. November 9,
2011.
Year(s) Of Engagement Activity 2011
URL http://dairy.ahdb.org.uk/news/news-archive/2011/november-2011/uk-food-and-farming-benefits-from-rese...
 
Description Roslin Reporter Dec 11 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Highlighting UK funded research by Roslin scientists who report that genetic resistance to bovine TB exists with published evidence and collaborations with researchers in the Republic of Ireland. The significance of the combined research is that in the future it will be possible to select animals more resistant to bTB and/or avoid animals that are highly susceptible.
Year(s) Of Engagement Activity 2011
URL http://www.roslin.ed.ac.uk/news/2011/12/22/roslin-reporter-december-2011/
 
Description Royal Highland Show 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Dr Hope, Prof Glass and PhD student prepared a joint poster and exhibition stand at the Royal Highland Show
Year(s) Of Engagement Activity 2012
 
Description Stakeholder Workshop University of Warwick 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact ~ 50 stakeholders attended this meeting which showcased research conducted under the BBSRC CEDFAS initiative: Contribution: Bermingham et al Bovine TB - a genetic simulation study for interval censored single intradermal comparative tuberculin test data. Bovine TB: hosts, pathogens and environments.
Year(s) Of Engagement Activity 2010
 
Description The Roslin Institute Open Doors Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Prof Hope and Glass presented a joint poster at the Roslin Institute Open Doors Day Sept 2012, highlighting different aspects of research aimed at combating bovine tuberculosis (bTB) in the UK. They also presented an exhibition stand highlighting their collaboration with Prof Gary Entrican & his colleagues at the Moredun Research Institute expanding the range of tools and resources for ruminant immune correlates of protection and resistance. All of this research is aimed at developing more effective vaccines and also selection for improved bTB resistance. Following this exhibition, a school student came to the Roslin Institute to pursue a CREST award with Prof Glass's supervision.
Year(s) Of Engagement Activity 2012