Is multistrain infection by Dichelobacter nodosus important in the severity of footrot and in the management of disease?

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

Footrot causes lameness in sheep. This debilitating disease causes sheep to lose weight and produce less milk so that their lambs grow slowly. Footrot is very common in the UK, affecting >98% of sheep flocks, with ~3 million sheep becoming lame/year. Footrot is caused by Dichelobacter nodosus, an anaerobic bacterium, that causes inflammation of the skin in a sheep's foot: this causes lameness. In some cases damage is so severe that the hoof horn separates from the living tissue inside the foot and exposes this flesh (severe footrot, SFR). It is an infectious disease that spreads between sheep, and sheep can become lame repeatedly because immunity is poor. Consequently footrot is an important cause of reduced productivity and poor welfare in sheep. Footrot costs the UK industry ~£80 million/year and is one of the most costly diseases in sheep farming globally.

Whilst we know D. nodosus causes footrot we also know that it is present on healthy feet and so does not always cause disease. Some D. nodosus strains are more able to cause severe disease than others. In the laboratory strains are labelled virulent (can cause SFR) or benign (cannot cause SFR) because of genetic markers in the bacteria, however, this is classification does not match disease that we see in sheep.

Footrot is present all year round (endemic) in most areas of the UK, appearing as a series of mini-epidemics throughout the year. Yet, in some parts of the world farmers have eradicated footrot from their flock. This is difficult in the UK because footrot is present in so many flocks, persists in our temperate climate and is spread between flocks by movement of sheep between farms, which is common in the UK. Control is therefore a more feasible option for the UK. This can be done by separating diseased sheep, treating sheep promptly to prevent disease spread, by preventive footbathing in disinfectant and by vaccines (although the currently licensed vaccine is not effective if used alone). These do ot prevent disease.

Studies of all strains of D. nodosus on the feet of on healthy, inflamed and diseased feet show that increasing numbers of D. nodosus on inflamed skin is linked to increasing risk of the development of severe disease.

Here we propose that for disease to occur at least one virulent D. nodosus must be present and in sufficient numbers on a foot and conversely that control can be gained by reducing the number of D. nodosus and reducing the number of virulence factors in the population of D. nodosus.

To test these ideas we will investigate the population of D. nodosus on the feet of sheep from flocks that are free from footrot, sheep that are changing from the diseased to non-diseased state and in flocks that are part of a clinical trial to reduce lameness by implementing a variety of new managements. In total ~11,000 swab samples of feet will be collected for analysis.

The analysis will use modern molecular techniques to determine whether D. nodosus is present in healthy flocks, whether different strains of D. nodosus (both virulent and benign) are present at different points in the progression of disease and whether the number of D. nodosus that are present on feet is linked to the disease state of the foot. We will then use these data to model what is happening on the feet, on sheep and within a flock to understand how the disease spreads and persists and how this might be prevented. The models will use sophisticated statistics to determine what factors are most important in disease progression and powerful mathematics to determine how these lead to disease spread and persistence.

This project includes scientists working to understand how communities of microbes change in time and space, with veterinary epidemiologists, who investigate how livestock diseases spread and can be controlled and modellers who determine how data we collect today can be used to most effectively treat and hopefully prevent disease in the future.

Technical Summary

Footrot, caused by Dichelobacter nodosus (Dn), costs the UK sheep industry >£80million pa: 98% of flocks have footrot and 3 million ewes are diseased pa. The current licensed vaccine includes 9/10 Dn FimA serogroups, offering 60% efficacy for 4 months. As vaccines contain fewer serogroups efficacy increases; flocks often have several serogroups.

Dn isolates are defined as benign or virulent based on specific virulence genes. Disease is also defined as benign or virulent, however, disease and isolate virulence are not well correlated: virulent isolates are detected in benign disease and vice versa. We propose that confusion has arisen because culturable isolates rather than whole community Dn have been studied and because isolate virulence has not been studied in longitudinal studies where disease dynamics would inform on temporal relationships between virulence of bacteria and disease.

Recent work in our group indicated that Dn load drives pathogenesis and that flocks with no disease still have detectable Dn. We hypothesise that total load and the whole community of virulent and benign Dn strains are key to understanding disease dynamics and to identify effective flock specific managements that provide resilience to disease. We will study total community, FimA and virulence of Dn using non-culture techniques: PCR, qPCR, MLVA fingerprinting and high-throughput sequencing. We will combine lab results with disease and management data from 3 epidemiological studies and use competing risks models to elucidate strain and virulence factors that drive disease progression and severity. A framework of stochastic mathematical models will be used to simulate optimal control strategies including the role of varying number of serogroups / vaccine. Should our hypothesis be correct then in 3-5 years the sheep industry will have a strategy to control footrot using a combination of flock specific vaccine together with other managements to reduce load and increase resilience.

Planned Impact

Endemic and chronic bacterial diseases are a major health and welfare issue for both humans and animals and many appear to be associated with either polystrain or polymicrobial infections. In our project, we aim to understand the role of polystrain infections with Dichelobacter nodosus on the development and severity of disease (footrot) in sheep and gain insights into the pathogenesis and best control of footrot at flock level. Footrot has major economic, environmental and welfare impacts. Therefore the results from this project have potential to impact across a number of sectors, from fundamental and applied science to the actual management of foot health on sheep farms. The Pathways to Impact of this proposal describes how end-users and other stakeholders will be engaged.


Understanding chronic bacterial diseases: the context of current management of footrot.

This project will provide evidence that explains how the current management of footrot perturbs the D. nodosus community and particular attention will be paid to effective managements and possibly novel managements should the data suggest these may be possible. Suitable partners within the ARC (levy bodies, pharmaceutical companies) will be sought to exploit these ideas.

If our hypothesis proves to be correct and we clarify the interaction between D. nodosus and footrot by estimating load and the community of virulence factors independent from culture, then our results will have direct impact on the sheep industry (vets, agricultural advisors and farmers). Vets and farmers will understand that control of disease can be achieved by driving down load and that this might be achieved using a variety of routes identified from the project. Farmers and vets can identify those suitable for their specific farm and implement them immediately.


Polystrain diseases and the role of bespoke vaccines

In the short to medium term, specifically for footrot, the veterinary pharmaceutical companies will be provided with simulated scenarios for the likely value of bespoke FimA vaccines in control of footrot. These can be produced for a flock once the serogroups present are known and the project will elucidate whether and when in a flock production cycle they would be most effective. The antigens are developed but clinical trials would be necessary before such products were used on farms.

In the longer term, all parties interested in polystrain diseases with poor immunity will have a novel strategy to consider investigation and management of polystrain infections.

This project, while based in the strategic science of understanding and controlling footrot, has the potential to impact both fundamental and strategic science across many fields. It will provide a model for investigating, understanding and potentially exploiting polystrain diseases and in the use of cutting-edge scientific approaches to tackling real-world problems in a coherent multidisciplinary fashion.

Publications

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Clifton R (2016) On the treatment, control and elimination of ovine footrot: a comparative review. in CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources

 
Description A mathematical model on footrot dynamics using bacterial load at the foot level has been developed and published. It is currently being optimised with further environmental and climate parameters to improve our understanding of how disease dynamics change in different environmental conditions and has highlighted the influence of rainfall on disease spread.
Exploitation Route Too early to say at this stage.
Sectors Agriculture, Food and Drink,Education,Environment,Pharmaceuticals and Medical Biotechnology

URL https://warwick.ac.uk/fac/sci/lifesci/research/greengroup/currentresearch/footrotdynamics
 
Description ISCF Agri-food Technology Catalyst Seeding Catalyst Award came as further funding. The Agri-Food Technology Seed Catalyst Award enabled us to meet animal health companies to discuss vaccines against footrot in sheep in the UK. We also contacted and visited the UK Veterinary Medicines Directorate to understand the requirements that need to be fulfilled to develop and market vaccines. Overall, the Seed Catalyst Award enabled us to identify that further pre-competitive research is required. We aim to proceed with this through publications from BBSRC BB/M012980/1 award and a future PhD, the design of which has been developed through information gained from the Seed Catalyst Award.
First Year Of Impact 2017
Sector Agriculture, Food and Drink,Education,Environment,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Development of new information on control of footrot and lameness for AHDB Beef & Lamb
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Bulletin sent to all 16000 members of sheep Better Returns Programme in England Written by PhD CASE students and Green Impact - Reduction in the number of sheep becoming lame, better health and productivity, economic gain to farmers
URL http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/07/BRP-Focus-on-lameness.pdf
 
Description Lecture to farm animal vet students on management of footrot
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact 70 students attended the talk and heard new information on management of footrot and lameness
 
Description On farm event to 28 farmers of one veterinary practice in worcestershire
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact the 28 farmers had new information on how to manage footrot and lameness in sheep
 
Description Technology exchange event to farmers Feb 2016
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact 67 farmers attended the one day event, 81% stated they would change management of footrot as a result of what they heard
 
Description BBSRC GCRF
Amount £23,535 (GBP)
Funding ID BB/GCRF-IAA/17/22 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 02/2018
 
Description BBSRC-GCRF
Amount £150,000 (GBP)
Funding ID BBSRC-GCRF-IAA/22 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 03/2017
 
Description ISCF Agri-food Technology Catalyst Seeding Catalyst Award
Amount £24,732 (GBP)
Funding ID BB/SCA/Warwick/17 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2017 
End 02/2018
 
Description AHDB 
Organisation Agricultural and Horticulture Development Board
Country United Kingdom 
Sector Public 
PI Contribution We work closely with AHDB Beef & Lamb providing summaries of research that are farmer friendly. Myself and PhD students attend farmer shows and events and talk to farmers. We work with AHDB to prepare knowledge exchange material
Collaborator Contribution AHDB are the CASE partner on a number of PhDs supporting industry relevant research on footrot and mastitis in sheep, giving students experience of an SME and talking to farmers to explain research
Impact http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/03/BRP-Reducing-lameness-manual-7-080316.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/08/brp-Decision-tree-for-lameness-270814.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/07/BRP-Focus-on-lameness.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/07/brp-Lameness080714.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/12/BRP-Udder-health-leaflet-181214.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/07/BRP-plus-Understanding-mastitis-in-sheep-180716.pdf
Start Year 2006
 
Description AHDB 
Organisation Agricultural and Horticulture Development Board
Country United Kingdom 
Sector Public 
PI Contribution We work closely with AHDB Beef & Lamb providing summaries of research that are farmer friendly. Myself and PhD students attend farmer shows and events and talk to farmers. We work with AHDB to prepare knowledge exchange material
Collaborator Contribution AHDB are the CASE partner on a number of PhDs supporting industry relevant research on footrot and mastitis in sheep, giving students experience of an SME and talking to farmers to explain research
Impact http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/03/BRP-Reducing-lameness-manual-7-080316.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/08/brp-Decision-tree-for-lameness-270814.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/07/BRP-Focus-on-lameness.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/07/brp-Lameness080714.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2014/12/BRP-Udder-health-leaflet-181214.pdf http://beefandlamb.ahdb.org.uk/wp/wp-content/uploads/2016/07/BRP-plus-Understanding-mastitis-in-sheep-180716.pdf
Start Year 2006
 
Description Animal Welfare Research Network (AWRN) 
Organisation University of Bristol
Department Advanced Composites Centre for Innovation and Science (ACCIS)
Country United Kingdom 
Sector Academic/University 
PI Contribution Professor Laura Green is a co-investigator on the AWRN
Collaborator Contribution on the organising committee for the network. In 2016, organised a speed dating session at the first event In 2017, speaking on grant writing skills at the annual meeting In 2017, organised for neuroscientists to speak at an interdisciplinary workshop between neurobiology and welfare
Impact none
Start Year 2016
 
Description 09/02/2016 University of Warwick Green Group organised farmer meeting to discuss lameness in sheep 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Approximately 100 farmers attended a meeting arranged by our research group to discuss lameness in sheep. The farmers were put into groups of about 8 with one of our research group present in each farmer group. There was a presentation on our findings from our group's research and then times for discussion on various aspects like treatment and prevention of lameness where farmers could discuss their approaches and perhaps what they could do differently. This was positively received and there was very good feedback from the farmers who found it very useful and we learnt a great deal from the engaging discussions.
Year(s) Of Engagement Activity 2016
 
Description 18/11/2017 AHDB Beef and Lamb Sheep Breeders Round Table 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact I presented a poster on my latest research to farmers who attended this meeting on all aspects of sheep breeding. We also engaged farmers with our recommendations on managing lameness in sheep.
Year(s) Of Engagement Activity 2017
 
Description 2016, 2017, 2018 Attending sheep shows to present our research to farmers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact I attended South Sheep Show in 2016 and South West Sheep Show in 2017 and will be attending a similar show in 2018. We present our research group's latest work to farmers and engage them in discussions about what they do to manage lameness and what they could do differently.
Year(s) Of Engagement Activity 2016,2017,2018
 
Description 2017, 2018 Workshop on lameness in sheep to Cambridge Vet School students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact In 2017 I participated in presenting knowledge and advice on all aspects of lameness in sheep from the background of the disease to treatment and prevention. There were also activities where the students were split into two groups and given an example scenario of a sheep farmer and how he currently manages lameness and from seeing our presentation what recommendations would they give to the farmer. I will be doing this again in 2018.
Year(s) Of Engagement Activity 2017,2018
 
Description 30-31/10/2017 BBSRC Animal Research Club 5th Dissemination Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact ARC BBSRC industry club biannual events
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.bbsrc.ac.uk/innovation/sharing-challenges/arc/
 
Description 30-31/10/2017 BBSRC Animal Research Club 5th Dissemination Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact I won the prize for the best poster which I presented at the ARC meeting on the latest findings from my research.
Year(s) Of Engagement Activity 2017
 
Description Presentation to Lleyn pedigree sheep breeder's AGM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Presentation on managing footrot and mastitis in sheep
Year(s) Of Engagement Activity 2016
URL http://www.lleynsheep.com/
 
Description Public engagement science evening University of Warwick 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A 6 - 8pm evening meeting at the School of Life Sciences where the theme was microbiomes. One of five evening events in 2016-17
Year(s) Of Engagement Activity 2017