CUKPGP: Epidemio- and immunological perspectives and prophylactic potential of Mycobacterium bovis and M. paratuberculosis co-infections in cattle
Lead Research Organisation:
University of Nottingham
Department Name: School of Veterinary Medicine and Sci
Abstract
Mycobacterium bovis, a relative of the bacterium causing human tuberculosis is the causative agent of bovine tuberculosis. A related bacterium M. avium subsp. paratuberculosis (MAP) causesa chronic wasting enteritis in cattle and is thought to have a role in Crohn's disease in man. Bothbacteria and thier diseases remain major public health and/or economic problems in many countries, including the UK and P.R.China. The incidence of M. bovis infection is well documented whereas information on MAP is poor in many countries. It is likely that mixed infection with these two pathogens occurs with unknown consequences for the progress of both diseases. We have exploited a technology (a DNA-based microarray) that allows simultaneous detection of many micro-organisms in a sample simultaneously. Our assay allows the simultaneous detection of 13 mycobacterial species (including the two mentioned in this proposal), which will be applied in both countries to assess the incidence of infection with the individual pathogens and also of mixed infection.
We have also been interested for some time in the stimulation of the innate immune system shortly after infection and the consequences for subsequent infection by related and unrelated pathogens. Innate immunity is the initial host response to infection an is not a learned response but will occur in the same way to many different bacterial types. The presence of intracellular bacteria in the tissues confers a profound resistance for some time after infection against unrelated pathogens. The outcome of this work is the indication that live bacterial vaccines (e.g. live Salmonella vaccines which would not interfere with the standard skin test used for testing individual animals and for surveillance) might be used to confer rapid resistance to mycobacterial infection as an emergency protection measure. There is an indication that this approach might also be used therapeutically in some circumstances and has potential application for controlling human infection..
This project will involve (i) use of DNA microarray technology to survey the incidence of mixed and single mycobacterial infections in China and the UK, and (ii) an assessment of the immunological interaction between M. bovis, MAP and Salmonella early in infection and whether this approach might be used to protect against these two mycobacterial pathogens for periods when naïve animals might be exposed to infection.
We have also been interested for some time in the stimulation of the innate immune system shortly after infection and the consequences for subsequent infection by related and unrelated pathogens. Innate immunity is the initial host response to infection an is not a learned response but will occur in the same way to many different bacterial types. The presence of intracellular bacteria in the tissues confers a profound resistance for some time after infection against unrelated pathogens. The outcome of this work is the indication that live bacterial vaccines (e.g. live Salmonella vaccines which would not interfere with the standard skin test used for testing individual animals and for surveillance) might be used to confer rapid resistance to mycobacterial infection as an emergency protection measure. There is an indication that this approach might also be used therapeutically in some circumstances and has potential application for controlling human infection..
This project will involve (i) use of DNA microarray technology to survey the incidence of mixed and single mycobacterial infections in China and the UK, and (ii) an assessment of the immunological interaction between M. bovis, MAP and Salmonella early in infection and whether this approach might be used to protect against these two mycobacterial pathogens for periods when naïve animals might be exposed to infection.
Technical Summary
Mycobacterium bovis and M. avium subsp. paratuberculosis (MAP) in cattle, remain major public health and/or economic problems in many countries, including the UK and P.R.China. The incidence of M. bovis infection is well documented whereas information on MAP is poor in many countries. It is likely that mixed infection with these two pathogens occurs with unknown consequences for the progress of both diseases. We have developed a DNA-based microarray that allows simultaneous detection of 13 mycobacterial species, which will be applied in both countries to assess the incidence of infection with the individual pathogens and of mixed infection.
We have been interested for some time in the stimulation of the innate immune system shortly after infection and the consequences for subsequent infection by related and unrelated pathogens. The presence of intracellular bacteria in the tissues confers a profound resistance for some time after infection against unrelated pathogens. The outcome of this work is the indication that live, attenuated bacterial vaccines might be used to confer rapid resistance to mycobacterial infection as an emergency protection measure. There is an indication that this approach might also be used therapeutically in some circumstances and has potential application for controlling human infection..
This project will involve (i) use of high throughput microarray technology to survey the incidence of mixed and single mycobacterial infections in China and the UK, and (ii) an assessment of the immunological interaction between M. bovis, MAP and Salmonella early in infection and whether this approach might be used prophylactically to protect against these two mycobacterial pathogens for periods when naïve animals might be exposed to infection.
We have been interested for some time in the stimulation of the innate immune system shortly after infection and the consequences for subsequent infection by related and unrelated pathogens. The presence of intracellular bacteria in the tissues confers a profound resistance for some time after infection against unrelated pathogens. The outcome of this work is the indication that live, attenuated bacterial vaccines might be used to confer rapid resistance to mycobacterial infection as an emergency protection measure. There is an indication that this approach might also be used therapeutically in some circumstances and has potential application for controlling human infection..
This project will involve (i) use of high throughput microarray technology to survey the incidence of mixed and single mycobacterial infections in China and the UK, and (ii) an assessment of the immunological interaction between M. bovis, MAP and Salmonella early in infection and whether this approach might be used prophylactically to protect against these two mycobacterial pathogens for periods when naïve animals might be exposed to infection.
Planned Impact
The impact of the proposed research is difficult to quantify. We are proposing that the exploitation of our results will lead to:
(i) (i) Improved accuracy of diagnosis of bovine TB and a better understanding of the role of mixed infections in evaluating the results of the currently used SCITT. Mixed infections undoubtedly occur in the UK and there is evidence for this in PRC, leading to
(ii) (ii) Impetus to introduce control measures against paratuberculosis in cattle in PRC and the UK, which could lead to
(iii) (ii) an associated reduction in the incidence of Crohn's disease in man in both countries and
(iv) (iv) a longer term benefit from exploiting the protective effect of providing animals with short term protection through vaccination with an unrelated vaccine such as an attenuated Salmonella for susceptible animals following introduction of a potentially infected animal to a herd/flock. This approach may be useful for valuable stock in the early stages of a control regimen. This approach to emergency protection could also be applied profitably to man in many parts of the world.
If the technology is adopted by regulatory authorities there will be initial gains through the sales of microarrays and associated equipment.
The financial impact of bovine TB in the UK is difficult to extrapolate to the PRC since the major problem in the UK centres on a specific wild animal maintenance reservoir. The cost to the UK is probably in excess of £90M p.a. and estimated at £1,200M for China. The impact of Johne's disease (paratuberculosis) in the UK is also difficult to estimate as a result of inaccurate estimates of its prevalence. Extrapolating the crude estimate of costs from the UK (£13M p.a. for 5.4M cattle) to PRC gives a cost of more than £300M p.a. for a cattle population of more than 130M. A proportion of this is thought to contribute to Crohn's disease in man. The estimated number of human cases in the UK is 35,000 with a cost of ca. £1.5M p.a., which is potentially a gross underestimate, and leading to a corresponding figure of £50M p.a. for PRC. Our approach will initially provide more accurate determination of the incidence of these economically important diseases in cattle in both countries and should contribute to reducing these figures, although it is difficult to estimate by how much.
The impact on human health through rapid protection and reduction in risk associated with exposure to infected cases is also difficult to estimate There are an estimated 8.8 million cases of TB in the world (http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Tuberculosis/TBWorldwideData/; http://www.who.int/mediacentre/factsheets/fs104/en/index.html) with the majority of cases in Africa and South East Asia, and therefore the potential for substantial impact
(i) (i) Improved accuracy of diagnosis of bovine TB and a better understanding of the role of mixed infections in evaluating the results of the currently used SCITT. Mixed infections undoubtedly occur in the UK and there is evidence for this in PRC, leading to
(ii) (ii) Impetus to introduce control measures against paratuberculosis in cattle in PRC and the UK, which could lead to
(iii) (ii) an associated reduction in the incidence of Crohn's disease in man in both countries and
(iv) (iv) a longer term benefit from exploiting the protective effect of providing animals with short term protection through vaccination with an unrelated vaccine such as an attenuated Salmonella for susceptible animals following introduction of a potentially infected animal to a herd/flock. This approach may be useful for valuable stock in the early stages of a control regimen. This approach to emergency protection could also be applied profitably to man in many parts of the world.
If the technology is adopted by regulatory authorities there will be initial gains through the sales of microarrays and associated equipment.
The financial impact of bovine TB in the UK is difficult to extrapolate to the PRC since the major problem in the UK centres on a specific wild animal maintenance reservoir. The cost to the UK is probably in excess of £90M p.a. and estimated at £1,200M for China. The impact of Johne's disease (paratuberculosis) in the UK is also difficult to estimate as a result of inaccurate estimates of its prevalence. Extrapolating the crude estimate of costs from the UK (£13M p.a. for 5.4M cattle) to PRC gives a cost of more than £300M p.a. for a cattle population of more than 130M. A proportion of this is thought to contribute to Crohn's disease in man. The estimated number of human cases in the UK is 35,000 with a cost of ca. £1.5M p.a., which is potentially a gross underestimate, and leading to a corresponding figure of £50M p.a. for PRC. Our approach will initially provide more accurate determination of the incidence of these economically important diseases in cattle in both countries and should contribute to reducing these figures, although it is difficult to estimate by how much.
The impact on human health through rapid protection and reduction in risk associated with exposure to infected cases is also difficult to estimate There are an estimated 8.8 million cases of TB in the world (http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/Tuberculosis/TBWorldwideData/; http://www.who.int/mediacentre/factsheets/fs104/en/index.html) with the majority of cases in Africa and South East Asia, and therefore the potential for substantial impact
Organisations
| Description | We have now developed a comprehensive microarray for mycobacterial species which may be applied across host species boundaries. This is being done in association with colleagues at China Agricultural University. They have found by PCR that cattle are not infrequently co-infected with M. tuberculosis in addition to M. bovis. We have more recently shown that the sensitivity of the array is at times comparable to that of a PCR and at times exceeds this. We have more recently found that positive signals may be obtained with saliva. We found evidence of M. bovis, BCG and in some cases co-infection with both, in Chinese cattle. |
| Exploitation Route | Application through identification of mycobacterial species from pure cultures of from in vivo samples. both for human, cattle and other species. |
| Sectors | Agriculture, Food and Drink |