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The molecular basis and impact on host response of phenotypic variation across Mycobacterium bovis molecular types - SE3232

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.

Technical Summary:
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.
Mycobacterium bovis is the causative organism of Bovine Tuberculosis (bTB), a major endemic disease of the UK cattle
population. Current disease incidence trends and government expenditure on the bTB control strategy are unsustainable,
requiring novel approaches if we are to control the disease. To achieve this we urgently need an understanding of the
reasons why the current control strategy is not working. Molecular epidemiology of M. bovis isolates has revealed the
emergence of expanding clones of the pathogen in different regions of Great Britain (GB). Studies using genome,
transcriptome, and metabolome analyses across the M. bovis population have shown that clones exist which have
distinct phenotypic characteristics. Our hypothesis is that the success of these emerging clones may be due to their
ability to modulate the host response to infection. To address this we will use a combination of host and pathogen
transcriptomics, cytokine and cell signalling assays, and genetic manipulation of the pathogen to determine the role of
pathogen variation in host response.
The key aims of this proposal are therefore
(1) to determine the impact of M. bovis molecular types on the bovine innate immune response and
(2) to identify the pathogen constituents that modulate this response.
This will be achieved through the following interlinked objectives:
Objective 1. Do distinct molecular types of M. bovis induce differential innate immune responses in the bovine host?
Objective 2. What are the constituents of the pathogen that trigger these responses?
Objective 3: Validation of immunomodulatory mechanisms
Objective 4: Data Management
This project will therefore provide underpinning research to inform GB disease control policy and further the
understanding of bTB pathogenesis.
Project Documents
• OTH - Other : SE3232   (2k)
Time-Scale and Cost
From: 2007

To: 2010

Cost: £130,045
Contractor / Funded Organisations
BBSRC Central Office
Animal Diseases              
Animal Health              
Bovine Tuberculosis              
Molecular Biology              
Plants and Animals              
Fields of Study
Animal Health