US-UK Collab: Mycobacterial Transmission Dynamics in Agricultural Systems: Integrating Phylogenetics, Epidemiology, Ecology, and Economics

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


Mathematical modeling of disease transmission is an important tool in studying infectious disease control; however, parameter estimation from field data is often difficult to quantify, especially with complex diseases. Whole-genome sequencing has become faster and more affordable in recent years, thanks to Next-Generation Sequencing techniques. As large databases of sequenced pathogen isolates become available, infectious disease epidemiologists will be able to use these databases, which are more fine-grained than previous serotyping methods, to improve our understanding of transmission dynamics. However, a general methodology is not yet available for such detailed data in bacteria with slow transmission timescales. This project proposes to develop a quantitative methodology for incorporating whole genome sequence (WGS) data into bacterial transmission models. For this, isolates will be used from mycobacterial infections in agricultural systems in the US and UK. Mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis (MAP) and M. bovis (bovine tuberculosis or bTB), are usually studied in simple one-host systems. Mycobacterial disease is extremely difficult to control due to long latent periods, poor diagnostic sensitivity, wildlife and environmental reservoirs of infection, and heterogeneous strain infectiousness. The key to controlling these diseases is believed to be an integrated approach to understand the pathways through which pathogen transmission occurs at all levels in an ecosystem: within animals, between individual animals, between livestock and wildlife, and between livestock and the environment. A generalized, multi-scale methodology is proposed for determining transmission dynamics using WGS data and phylodynamics. These dynamics will be incorporated into predictive models of disease transmission and control within an economic framework, to help decision-makers make informed control choices.

Technical Summary

We will develop a new multi-scale model of infection transmission and control which will be used to better understand the principles, dynamics, and impacts of multi-host infections (particularly mycobacterial infections) at multiple levels. These models will be developed in an integrated, phylodynamic parameter estimation framework, using mathematical models that incorporate both our detailed farm and phylogenetic data. In particular, our work will provide a general framework for modeling infection dynamics of slow-moving pathogens within livestock herds and the connection to both wildlife populations and environmental reservoirs that can affect the dynamics of transmission and control. Our work will be based on unique and innovative data collection methods and data analyses. We will test our methods using expansive isolate collections and precise data on two mycobacterial infections: Mycobacterium avium subsp. paratuberculosis (MAP), the cause of Johne's disease (JD) in ruminants, and Mycobacterium bovis (M. bovis), the causal agent of bovine tuberculosis (bTB). Bovine tuberculosis will be studied in cattle and white-tailed (WT) deer (Odocoileus virginianus) in the US and compared to bTB in cattle and Eurasian badgers (Meles meles) in the UK, while MAP will be studied in dairy cattle and their environment in both the US and UK. These infections are active in complex ecosystems and affect human populations through direct contact, economic impact, and potential contamination of the food supply. By comparing across pathogens, we can examine the impact of the difference between wildlife reservoirs (M. bovis) and environmental reservoirs (MAP), with their differing mutation rates4 while determining the general principles involved in integrating WGS and epidemiological models.

Planned Impact

Transformative research in phylodynamics and disease ecology is proposed to improve our understanding of bacterial infection dynamics by developing 1) a generalized methodology for incorporating WGS data into transmission models, 2) a generalized ecosystem approach to modeling infectious diseases with agricultural production and economic components, and 3) research methods for modeling transmission dynamics in complicated multi-scale systems. This project will integrate innovative phylodynamic techniques with novel data collection and analysis across various scales in the US and UK to determine the minimum necessary data requirements for this model type. The results will allow for design of cost-effective data collection programs, which will be valuable in develop countries but essential in many livestock-dependent low-income countries.

phylodynamic framework at the core of this work will have broad use in public health policy and practices through identifying important factors in multi-host, systems; the generality of the framework will allow it to be adapted broadly to bacterial diseases affecting humans and animals. This interdisciplinary work will promote a cross-fertilization of ideas amongst students, researchers and faculty in molecular biology, epidemiology, ecology, and economics. The molecular biologists, epidemiologists, ecologists and economists in the team will collaborate closely to develop the techniques for this work. Other research-related education and outreach activities specific to this work will include workshops at NIMBioS, short-courses on transmission for veterinarians, and an intensive graduate-level course on endemic disease modeling. Furthermore, members of the group actively participate in science educational programs for 7th-9th grade girls in the Ithaca, NY community and in education for school-age children in the UK, as well as professional development classes in many countries.

At the completion of the project, a methodology will have been developed for multi-scale generalized systems modeling of multi-host infectious diseases in an ecosystem that includes livestock, environmental, wildlife, and economic components with a particular application in mycobacterial diseases and their control. A large impact is expected in core phylogenetic and mathematical epidemiology areas, including multi-scale modeling and inference from WGS data. In the process high school, undergraduates, graduate students and post-doctoral fellows will have been trained and enthused in the use of this approach.

Related Projects

Project Reference Relationship Related To Start End Award Value
BB/M01262X/1 01/09/2014 14/09/2017 £379,635
BB/M01262X/2 Transfer BB/M01262X/1 15/09/2017 14/08/2019 £109,862
Description Analysis of the evolutionary dynamics of M bovis in Michigan deer cattle and elk has shown that elk are unlikely to have had an impact on the amount of Bovine Tb in Michigan cattle. There are considerable tensions between hunting lobbies and the cattle industry in Michigan. Elk are a 'flagship' hunting species in Michigan, and demonstrating in our detailed studies with novel deep sequence data, that there is no evidence for elk to have a role in transmission to cattle helps to refine policies towards controlling Tb.
Exploitation Route Replication of our methods could easily be used in other situations where interpretation of slowly evolving pathogens means that the more standard approaches (developed for RNA viruses in a large part) are less robust. There is interest from the Michigan Dept of Agricultural and Rural Development (MDARD) and Department of Natural Resources (MDNR) to use our data and analyses for ongoing analysis of bovine TB outbreak in Michigan cattle (MDARD), and to inform control of bovine TB in Michigan deer (MDNR).
Sectors Agriculture, Food and Drink,Healthcare

Description I) The mycobacterial diseases workshop held in 2018 was attended by non-academics including individuals in government and in professions. As such, it helped persons outside of academia, with impact on government and private usage of outcomes to better understand the consequences of new types of data (in particular deep sequencing data for pathogens). II) As a result of the results from the project, representatives from the Michigan Dept of Natural Resources (Dr. D. O'Brien) and Agriculture and Rural Development (Dr N. Barr) have agreed to act as collaborators on a US-UK EEID proposal that is currently under review. The new proposal would continue the work from this project as part of an overall assessment of the role of human management decisions in controlling disease, as the sequence data and analyses provide the best available data for assessing 'who infected whom' which is vital for understanding the efficacy of the human decision-making.
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Education,Government, Democracy and Justice
Impact Types Policy & public services

Description Member of Defra's Science Advisory Council
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact As a member of Defra's Science Advisory Council, I provide comments on a wide variety of Defra science-related policies and draw upon both my personal research experience, but also the broader research community at the Roslin Institute
Description Collaboration with Dr. Suelee Robbe-Austerman USDA-APHIS 
Organisation U.S. Department of Agriculture USDA
Department Animal and Plant Health Inspection Service
Country United States 
Sector Public 
PI Contribution From our project, we aided in the development of bioinformatics tools in partnership with USDA-APHIS that they are using for analysing collected mycobacterial sequences at USDA-APHIS.
Collaborator Contribution Our partners have provided free access to their sequence databases, as well as contextual information and advice.
Impact As a result we have recently submitted a new US-UK EEID proposal (decision pending) that builds on the previous work.
Start Year 2014
Description BBSRC, Defra, NC3Rs Bovine tuberculosis Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact This workshop was organized by BBSRC-Defra-NC3Rs in order to bring researchers working on bovine tuberculosis (bTB) together to promote knowledge exchange, networking and to contribute to the development of a number of roadmaps for bTB. I presented a poster entitled "The use of Next Generation Sequencing to understand bovine Tuberculosis transmission in a multi-host system".
Year(s) Of Engagement Activity 2017
Description Ecology and Evolution of Infectious Diseases Conferences 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I have participated in the International EEID conference where I presented a poster entitled "The use of Whole-Genome-Sequencing to understand bovine Tuberculosis cross-species transmission patterns in Michigan, USA" an gave a lightning talk entitled: "Investigating bacterial transmission at the wildlife/livestock interface using genomic data: bovine tuberculosis in Michigan, USA", in 2016 and 2017, respectively.
Year(s) Of Engagement Activity 2016,2017
Description ISVEE conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Participation in the 14th Conference of the International Society for Veterinary Epidemiology and Economics: Planning Our Future. I gave a talk entitled: "Estimating bacterial cross-species transmission in Michigan", which was followed by interesting questions and discussion. The participation in this conference also originated a blog post about "Multi-disciplinary interactions under the Mexican sun - reflections from the ISVEE conference" (

Participation in the 15th Conference of the International Society for Veterinary Epidemiology and Economics. I gave a talk entitled: "Understanding the emergence and evolution of Mycobacterium bovis in Michigan, USA", which was followed by interesting questions and discussion.
Year(s) Of Engagement Activity 2015,2018
Description Molecular Ecology Spotlight blog post on Salvador et al 2019 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The "Molecular Ecology Spotlight" is a popular science blog aimed at promoting especially interesting work published in the Molecular Ecology journal. A blog post was written by the blog staff highlighting the results of Salvador et al. 2019, characterising the epidemiology of M. bovis in Michigan cattle and deer.
Year(s) Of Engagement Activity 2019