Exploring the richness of Mycobacterium bovis strain diversity to decipher the epidemiology of bovine tuberculosis ecology

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Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is a multi-species infection that causes a serious burden on the cattle industry in Great Britain (GB), and throughout the world. Despite extensive control measures in cattle, the disease in cattle remains uncontrolled and now costs the UK government around £100 million per year. Control of the disease is governed by a National Strategy, published by Defra.Control is based around routine surveillance testing of living cattle and all those slaughtered in GB slaughterhouses. Routine surveillance is based around the use of a highly specific but relatively insensitive skin test. When infection is diagnosed, attempts are made to isolate M. bovis from skin test positive cattle, which are all slaughtered. M. bovis can be isolated from around 70% of all infected herds. Herds where infection is diagnosed are placed under movement restriction and all animals are then subjected to repeated skin testing until no further detectable infection is evident. One of the great challenges for control is that half of all farms in high incidence areas of England and Wales that are restricted, tested and released have recurrent disease within 3 years. It is unclear how much of this disease burden is associated with persistence in cattle or with reintroduction from wildlife, specifically badgers, whose infection is closely linked with that in cattle in high incidence areas of GB. Thus, a key question in bTB control in Britain relates to what the source of the infection is for herd. At the individual level, knowing this allows for specific measures to be put in place to prevent recurrence of infection. At the national level, understanding the sources of constant bTB challenge, allows for more general policy to be developed and targeted at the sources of this reinfection. Modern genetic methods provide great opportunities for forensic evaluation of outbreaks of diseases. Organisms causing disease can be genetically sequenced to determine their origins and relationships with other outbreaks and cases. Detailed genetic sequencing of bacteria that cause disease is now becoming common in human medicine to determine what optimal controls should be. New methods mean that this can be done in real time. The bacterium that causes bTB, M. bovis, has been evaluated routinely in in GB using traditional genetic methods over the last 20 years as part of surveillance. These studies have the surprisingly restricted distributions of different genetic types to be mapped in Britain - and hence to determine the likely origins of outbreaks that occur in low incidence areas (often associated with cattle movements); however, the classification is not fine grained enough to allow differentiation of local on-farm persistence of disease from that associated with introduction from relatively short distance cattle movements. Our work will use the amazing library of M. bovis isolates held by Defra's laboratory agency and will apply modern whole genome sequencing methods to 2000 carefully selected retrospective samples. We will use samples from recent routine surveillance from over GB, particularly focussing on farms where disease has been persistent, to evaluate the different drivers of persistence that so hamper our control efforts. We will also use samples from the randomised badger control trial where there is unparalleled availability of badger isolates and far more intensively parallel sampled cattle to reveal more details of the complex transmission dynamic between the two species, in order to allow more precise targeting of measures to prevent cattle becoming infected in the future. Our work will translate directly into Defra's plans for more intensive investigation and intervention on farms that repeatedly become infected in high incidence areas. The approaches that we develop will become, as in human medicine, part of the routine approaches taken when investigating disease.