The molecular basis and impact on host response of phenotypic variation across Mycobacterium bovis molecular types

Bovine tuberculosis (bTB) is one of the most difficult animal health problems that the farming industry in Great Britain faces today. The number of cattle infected with bTB has been increasing year on year by 18%, which leads to serious losses for affected farms due to the slaughter of infected animals and the imposition of cattle movement restrictions. Government spending on disease surveillance and compensation to farmers has also been following this upward trend, with spending over 2004-2012 expected to top £1 billion. From these statistics it is clear that the current disease control strategy is not working, yet the reasons for this are not obvious. One possibility is that new forms of the causative agent of bTB, Mycobacterium bovis, have evolved in GB that are able to circumvent the current control measures. Research by the VLA has found that evidence for this latter scenario is supported by the presence of a range of different types of M. bovis circulating in GB that seem to be successful in spreading around the country from their original place of isolation. This proposal sets out to determine whether these diverse types of M. bovis interact with the immune system of cattle in different ways, and so explain their success. To achieve this we will take advantage of the recent availability of the complete DNA sequences of both M. bovis and the bovine host. This will allow us to explore how the host and pathogen interact with each other at the level of individual molecules, and to build up a more detailed picture of how M. bovis causes disease in cattle. The information coming from this project will help government policy makers to develop new control strategies based on the exploitation of epidemiological information, and offers the chance to stop the upward spiral of bTB disease burden and linked expenditure in GB.

Bovine Tuberculosis (bTB) is one of the major endemic diseases affecting the UK cattle population, with disease incidence showing an 18% year-on-year increase and government expenditure on bTB control doubling every 4 years; new control strategies are desperately needed to halt this upward trend. The causative agent of the disease is Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex. Previous work has shown that distinct molecular types of M. bovis are circulating in GB, and that these types have distinct phenotypic traits. In this proposal we will extend these findings to determine the impact of strain molecular type on host immune response. We will determine the effect of strain type on the interaction with two key host immune cells, macrophages and dendritic cells, using global gene expression profiles, cytokine production, and signalling cascades as readouts. We will also determine whether the response of the pathogen to the initial stages of infection varies across strain type, and use this data to construct defined mutants so that the role of pathogen determinants in infection can be delineated. The outputs from this proposal could have a major impact on the way molecular epidemiology is used to both inform bTB policy and control disease in GB.