Integrated systems approach for preventing uterine disease in dairy

Lead Research Organisation: Swansea University
Department Name: Institute of Life Science Medical School

Abstract

Multi-pathogen infections of the uterus after parturition are endemic causing clinical uterine disease in 40% of dairy cattle and a further 20-40% develop subclinical disease each year. The number of animals requiring treatment is rising as milk production increases. Uterine disease causes infertility, delayed conception, disruption of ovarian cycles, involuntary culling for failure to conceive, and mortality, costing the EU dairy industry EURO1.4 billion/year. The cost to the animal is pain and suffering for several weeks. The cost to the environment is more greenhouse gas emissions, land and water degradation because more cattle have to be kept on farms to replace infertile animals. Research into uterine infection has been neglected compared with other major diseases; there are no vaccines or prevention strategies, and treatment relies on antibiotics and hormones. However, there has been an explosion of knowledge about innate and mucosal immunity in the last 10 years, which provides insights that can be exploited to prevent disease. Furthermore, our recent work has identified several potential strategies to prevent or limit this endemic disease that urgently need examining. Now is the strategic moment where concerted action between the partners is likely to have an impact on uterine disease. This project aims to translate novel strategies into potential products that limit the impact of uterine disease. We will pursue 3 objectives: 1. Refine our underpinning knowledge and tools for postpartum uterine disease in cattle. This includes refining and benchmarking our in vitro and in vivo models of disease; exploring the details of the microbes that infect the uterus, including our newly discovered endometrial pathogenic E. coli (EnPEC); and developing molecular tools to evaluate and diagnose disease. 2. Test candidate strategies to prevent or limit uterine disease using our in vitro and in vivo models. 3. Translate the best candidate strategies that prevent or limit uterine disease to pre-clinical field trials. The project addresses the first translational gap between basic science and the generation of ideas or products for animal health. We are fortunate to have support from our industrial partners, who also have the expertise to then take the results of the project to market for the benefit of all stakeholders.

Technical Summary

Multi-pathogen infections of the uterus after parturition are endemic causing clinical uterine disease in 40% of dairy cattle and a further 20-40% develop subclinical disease each year. The number of animals requiring treatment is rising as milk production increases. Uterine disease causes infertility, delayed conception, disruption of ovarian cycles, involuntary culling for failure to conceive, and mortality, costing the EU dairy industry EURO1.4 billion/year. The cost to the animal is pain and suffering for several weeks. The cost to the environment is more greenhouse gas emissions, land and water degradation because more cattle have to be kept on farms to replace infertile animals. This project aims to translate novel strategies into potential products that limit the impact of uterine disease. We will pursue 3 objectives: 1. Refine our underpinning knowledge and tools for postpartum uterine disease in cattle. 2. Test candidate strategies to prevent or limit uterine disease using our in vitro and in vivo models. 3. Translate the best candidate strategies that prevent or limit uterine disease to pre-clinical field trials.

Planned Impact

Fit to EMIDA goals 1. Supports EU collaboration at a strategic point in research development for a neglected microbial disease of livestock. 2. Coordinated transnational approach provides a critical research mass to accelerate progress to prevent uterine disease, which costs the EU EURO1.4 billion each year. 3. Reducing the incidence and severity of a common infection by vaccination or regulation of mucosal immunity, will: a. Improve cattle health, fertility and productivity b. Enhance the sustainability of EU dairy farming c. Reduce the environmental footprint of dairy cattle d. Improve animal welfare e. Increase European animal health industry competiveness f. Translate basic science to products that address an endemic disease of livestock g. Develop novel diagnostic tools for subclinical disease h. Reduce the reliance on antimicrobial and hormone treatments 4. Step up durable reproductive disease research in the EU. 5. Bring substantial funding to the EU from Pfizer's group of world-leading pharmaceutical companies.

Publications

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Healey GD (2016) Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis. in Journal of immunology (Baltimore, Md. : 1950)

 
Description The iPUD project worked as an integrated collaboration between academic groups and a large industrial partner (Pfizer Animal Health, which was divested from Pfizer Inc. during the lifetime of the project to form the company Zoetis).
Main Activities
In Work Package 1 (WP1), we refined underpinning knowledge about innate immunity and inflammation in the bovine endometrium and immune cells. We developed an ex vivo model to study bovine endometrium, and refined our in vitro culture systems for endometrial cells and immune cells. We sequenced several bacterial genomes and made important discoveries about the ecology and virulence factors of the microbes. We developed for the first time a robust and repeatable in vivo model of uterine disease in lactating cows, which is used for product development. We are finalising the diagnostic gene panels for healthy and diseased endometrium.
In WP2 we used the models developed in WP1 to identify candidate strategies to limit the severity of uterine disease. We first used our ex vivo and in vitro models to screen 49 active molecules, across multiple mechanisms of action. Following extensive testing in 3 countries, one of the mechanisms of action was selected to go forward to the animal model, along with a prototype vaccine. The remaining mechanisms of action were published or shared by open innovation. The animal model was used to evaluate active molecules from the candidate mechanism of action and the vaccine. The animal model was used to test efficacy against uterine disease, and both approaches have gone to pre-clinical studies in WP3.
In WP3 we translated our selected two strategies to pre-clinical trials. Multiple in vivo and in vitro studies were completed to evaluate safety and prepare data for regulatory authorities for approval for a field study. Both strategies are now in early product development in industry, and the industrial partner has already committed twice the original agreed budget to this work. The field study is scheduled for the end of 2014 pending site determination limitations.
The overarching WP4 was where we established the framework for international collaboration including a Project Management Board and an External Advisory Group. We held 14 meetings of the whole project group, including 8 meetings in-person over 2 days each, in France.

International Collaboration
There was a wide range of real interaction between research groups, as evidenced in multiple joint publications (see Section 5). This included exchange of bacteria, exchange of biological samples and active molecules, and collaborative research projects. Added value included training of staff within the EU and the formation of a firm foundation for our research, as evidenced by team members winning 3 further grants within the EU.
Exploitation Route Confidential clinical trials of 2 products. These trials were successful and Zoetis are taking commercial decisions.
Sectors Agriculture, Food and Drink,Healthcare

URL https://sites.google.com/site/professormartinsheldon/projects/ipud-project
 
Description Two products are in pre-clinical trials and will move to clinical trails Q4 2014 A patent was applied for by Zoetis Inc. Clinical trials confirmed the effectiveness of the compounds. There is an issue about the cost of compound relative to the ability of farmers to pay for a product. Zoetis are taking commercial decisions.
First Year Of Impact 2013
Sector Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description MSD 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution We are exploring how to help Merck Inc (MSD) to prevent uterine disease in dairy cattle.
Collaborator Contribution Merck are seeking novel methods to increase the robustness of dairy cattle against uterine disease.
Impact Series of teleconferences and sharing of data and standard operating procedures.
Start Year 2018
 
Description Open innovation 
Organisation University of Parma
Country Italy 
Sector Academic/University 
PI Contribution ERASMUS collaboration on viral sensing in the endometrium
Collaborator Contribution Viral biotype provision and testing.
Impact Paper to be published
Start Year 2012
 
Description Supplying Trueperella pyogenes isolates 
Organisation French National Institute of Agricultural Research
Department INRA Rennes Centre
Country France 
Sector Public 
PI Contribution We supply fully sequenced isolates of our clinical isolates of Trueperella pyogenes for research in vitro and in vivo
Collaborator Contribution We are conducting collaborative projects, and seeking further funding in some cases.
Impact In vivo animal model (Confidential IP)
Start Year 2015
 
Description Supplying Trueperella pyogenes isolates 
Organisation University of Florida
Department Department of Animal Science
Country United States 
Sector Academic/University 
PI Contribution We supply fully sequenced isolates of our clinical isolates of Trueperella pyogenes for research in vitro and in vivo
Collaborator Contribution We are conducting collaborative projects, and seeking further funding in some cases.
Impact In vivo animal model (Confidential IP)
Start Year 2015
 
Description Supplying Trueperella pyogenes isolates 
Organisation Zoetis
Country United States 
Sector Private 
PI Contribution We supply fully sequenced isolates of our clinical isolates of Trueperella pyogenes for research in vitro and in vivo
Collaborator Contribution We are conducting collaborative projects, and seeking further funding in some cases.
Impact In vivo animal model (Confidential IP)
Start Year 2015
 
Description iPUD 
Organisation French National Institute of Agricultural Research
Country France 
Sector Public 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Description iPUD 
Organisation Gottfried Wilhelm Leibniz Universität Hannover
Country Germany 
Sector Academic/University 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Description iPUD 
Organisation Moredun Research Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Description iPUD 
Organisation Pfizer Ltd
Department Pfizer Animal Health
Country Global 
Sector Private 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Description iPUD 
Organisation University of Florida
Country United States 
Sector Academic/University 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Description iPUD 
Organisation University of Glasgow
Department School of Veterinary Medicine Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Innate immunity in the endometrium
Collaborator Contribution Microbiology, clinical trials
Impact See https://sites.google.com/site/professormartinsheldon/projects/ipud-project
Start Year 2009
 
Title THE USE OF STATINS IN TREATING BACTERIAL UTERINE DISEASE 
Description The present invention provides a method for preventing, treating, delaying the onset or lessening the severity of bacterial uterine disease, including metritis, endometritis and pelvic inflammatory disease, in mammals, such as cattle, sheep, goats, dogs, and cats. 
IP Reference US62/076,687 
Protection Patent application published
Year Protection Granted 2014
Licensed Commercial In Confidence
Impact Product Operating Plan within Zoetis Inc.
 
Description Uo3A 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact University of the third age meeting - talk on science and the science of infertility

I was asked to give further talks to local lay audiences
Year(s) Of Engagement Activity 2015