Bilateral BBSRC-SFI: Tackling a multi-host pathogen problem - phylodynamic analyses of the epidemiology of M. bovis in Britain and Ireland

Diseases that infect more than one host species can be particularly difficult to control, and well known examples include avian influenza (in wild birds, poultry and humans), rabies (in dogs and humans), Brucellosis (in livestock and humans) and Ebola virus (in primates and humans). If one or more of those is a wildlife species, control can prove particularly difficult. Wildlife are harder to observe, harder to access for purposes of disease control, and often we need to counterbalance the requirements of disease control with the needs of wildlife conservation. For all these reasons, identifying the root causes of disease transmission and quantifying the impact of disease control is a challenging problem in these 'multi-host' systems, a problem that is exacerbated when human management results in ecological disturbances that in themselves increase disease risk.

An increasingly important tool in disentangling potential sources and routes of transmission is the deployment of mass "whole genome sequencing" of the causative agent of disease, taken from infected individuals. By tracking changes in the genetic code of the disease agent as it passes from individual to individual, and combining them with computer models that take into account other information we have on the transmission of disease (e.g. who was in contact with whom, and when, and how long individuals are infectious for) these data provide the best opportunity to identify 'who infected whom' - if not on the individual level, then at least at a level that is impossible without this kind of information. Importantly, it helps us to identify how important the different species are in these multi-species systems and also helps us to best identify how to control the disease. However, because these technologies and these uses of them are still relatively new, it is important to have good, well studied systems on which we can test and understand how best to use them.

One disease problem which exhibits all these characteristics, has exceptional information and also represents an important problem in itself is bovine Tuberculosis (bTB) in cattle and badgers. BTB is estimated to cost the UK about £100 million per year, results in thousands of cattle slaughtered every year, and is a zoonotic risk to farmers, veterinarians and in particular individuals with compromising existing infections (e.g. HIV/AIDS). Badgers are known to be involved in the transmission of the disease to cattle and without some form of badger-targeted disease control, it will be impossible to eradicate. With any effective vaccine still many years away, badger culling is an important potential means of control but because badgers are a protected and much-loved species, it is highly controversial. This controversy is made worse by conflicting evidence regarding the value of culling, with trial culls in England suggesting that it induces a social 'perturbation effect' that makes culling impractical, while trials in the Republic of Ireland indicating it can be effective. In this project, we shall aim to build upon existing work and generate sequences for bTB in Irish cattle and badgers, taking advantage of the exceptional record they have of their badger population. Using mathematical models based on principles of 'social networks' to help us understand these data, we aim to contrast the control of bTB in Ireland, where badger culling has long been extensively used, with Northern Ireland and England, where it is not. This will allow us to estimate the potential benefit, if any, that badger culling could play in England, and the potential impact should culling efforts cease in Ireland. Thus this project will be of both immediate benefit to the control of bTB in cattle, but also have long term benefit in developing new approaches and insights that will improve our conceptual understanding of multi-host diseases, and the role that ecological disturbance plays in zoonotic disease emergence and spread.

Multi-host pathogen systems present challenges not found in diseases that primarily infect a single host species. The difficulties that arise when one or more hosts is wild, and particularly where control efforts can cause ecological disturbances that exacerbate disease incidence, are notorious, and are a problem for many zoonoses and diseases of livestock. Mass high throughput or 'whole genome sequencing' of pathogens has already transformed our understanding of many diseases, in particular rapidly mutating pathogens such as many RNA viruses. However, the application of this technology to more slowly mutating pathogens such as Mycobacteria, and in particular where the system is multi-host, remains a current challenge.

As such, the purposive generation of data and analysis of good model systems has broad potential benefit both in terms of methodological development and epidemiological insight. One system that contains an exceptonal epidemiological record and is an important problem in itself is bovine Tuberculosis (bTB) in cattle and badgers in Britain and Ireland. Control of disease by badger culling is an important option but is highly controversial, with evidence from the Republic of Ireland (RoI) pointing to it being an effective means of control, but from England suggesting it is not. Central to the scientific question is a need to understand the relative roles that badger density and social perturbation (due to culling) have on the transmission of disease to cattle. By sequencing large numbers of isolates in cattle and badgers from RoI, and taking advantage of the exceptional record they have of both the cattle and badger populations, we shall build on existing projects analysing data from GB and Northern Ireland, using phylodynamic approaches (based both on well established evolutionary approaches and bespoke models fitted using Bayesian inference techniques) to disentangle the roles of density and perturbation on the cattle epidemic in both GB and RoI.

Government stakeholders. Bovine tuberculosis (bTB) places a significant burden on national economies in Britain and Ireland with an estimated future cost of £1 billion over the next ten years. New insights or approaches generated by this project therefore have the potential to make a direct economic impact if they affect government policy and, in the long term, translate into more effective control strategies. In addition to monetary costs, the question of how to best control bTB, and in particular the use of badger culling, has become a hugely divisive, political issue. Any information that would help to place control strategies on more a science- and evidence-based footing, should therefore be valuable to policy makers.

Generally, benefits from this project to the public sector may include

I) insights into mechanisms of persistence and spread of the disease;
II) Risk factors influencing the distribution, size and re-occurrence of bTB outbreaks on farms;
III) evaluation of WGS as a potential tool for incorporation into future routine diagnostic and control programs
IV) Quantify the benefits of long term badger culling and it influences the badger-cattle interaction (perturbation)
V) Guidelines for bTB control, especially in terms of identifying methods to spatially target control and determine the extent of control required (both geographically, by species and by proportion of population)
V) Identification of unrecognised knowledge gaps and research priorities.

Cattle farming industry. Although there is legal compensation for cattle slaughtered as a result of testing positive for bTB, this covers only a fraction of the true cost, with a significant burden placed on farmers via the imposition of movement restrictions and the cost and effort associated with the multiple whole herd tests while the outbreak is being eradicated.

This project will address long-standing questions about bTB epidemiology, persistence mechanisms and herd risk factors. Where answers to these question can be used to improve management and control strategies, either through government policy or self-guided action, they will result in tangible benefits to the livestock industry. Wildlife conservation. The debate over the value of badger culling is an ongoing one, with sharply divided opinions on both sides, however it is currently considered one of the most important options for control of bTB. Better understanding of the role of badgers in the persistence of bTB will result in, at the very least, a more efficient approach to culling and/or provide better insight into the possible uses for vaccination.

Wider public. A large part of the public is generally familiar with the issues surrounding bTB, the cost it places on tax payers and farming communities and the debate about whether badger culling is a defendable control strategy on both practical and ethical grounds. By providing objective scientific information about some of the underlying processes, this project therefore has the potential to help shape public opinion on these issues. We would also hope that by demonstrating the value of using novel science and technology tools to answer questions of significant public interest, this work could play a part in highlighting the benefits of research, and the use of public funds, to society.

Academic Impact. For expected academic impact, see 'Academic beneficiaries'