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.
Organisations
- Swansea University (Lead Research Organisation)
- Department for Environment Food and Rural Affairs (Co-funder)
- Moredun Research Institute (Collaboration)
- University of Florida (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- Pfizer Ltd (Collaboration)
- Zoetis (Collaboration)
- Gottfried Wilhelm Leibniz Universität Hannover (Collaboration)
- University of Parma (Collaboration)
- MERCK (Collaboration)
- French National Institute of Agricultural Research (Collaboration)
People |
ORCID iD |
Iain Sheldon (Principal Investigator) |
Publications
Vitorino Carvalho A
(2016)
Analysis of STAT1 expression and biological activity reveals interferon-tau-dependent STAT1-regulated SOCS genes in the bovine endometrium.
in Reproduction, fertility, and development
Turner ML
(2012)
Immunity and inflammation in the uterus.
in Reproduction in domestic animals = Zuchthygiene
Sheldon IM
(2017)
Innate immunity and the sensing of infection, damage and danger in the female genital tract.
in Journal of reproductive immunology
Sheldon IM
(2011)
Innate immunity in the human endometrium and ovary.
in American journal of reproductive immunology (New York, N.Y. : 1989)
Sheldon IM
(2016)
Detection of Pathogens in Blood for Diagnosis of Sepsis and Beyond.
in EBioMedicine
Sheldon IM
(2018)
Symposium review: Mechanisms linking metabolic stress with innate immunity in the endometrium.
in Journal of dairy science
Sheldon IM
(2014)
Innate immunity and inflammation of the bovine female reproductive tract in health and disease.
in Reproduction (Cambridge, England)
Sheldon IM
(2014)
Genes and environmental factors that influence disease resistance to microbes in the female reproductive tract of dairy cattle.
in Reproduction, fertility, and development
Sheldon I
(2017)
Postpartum uterine infection and endometritis in dairy cattle
in Animal Reproduction
Saut JP
(2014)
Ovarian steroids do not affect bovine endometrial cytokine or chemokine responses to Escherichia coli or LPS in vitro.
in Reproduction (Cambridge, England)
Preta G
(2016)
Tethered bilayer membranes as a complementary tool for functional and structural studies: The pyolysin case.
in Biochimica et biophysica acta
Noleto PG
(2017)
Short communication: Glutamine modulates inflammatory responses to lipopolysaccharide in ex vivo bovine endometrium.
in Journal of dairy science
Lesage-Padilla A
(2017)
Maternal metabolism affects endometrial expression of oxidative stress and FOXL2 genes in cattle.
in PloS one
Healy LL
(2015)
Polarized Epithelial Cells Secrete Interleukin 6 Apically in the Bovine Endometrium.
in Biology of reproduction
Healey GD
(2016)
Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis.
in Journal of immunology (Baltimore, Md. : 1950)
Goldstone RJ
(2014)
Draft Genome Sequence of Trueperella pyogenes, Isolated from the Infected Uterus of a Postpartum Cow with Metritis.
in Genome announcements
Goldstone R
(2014)
Draft Genome Sequence of Escherichia coli MS499, Isolated from the Infected Uterus of a Postpartum Cow with Metritis
in Genome Announcements
Düvel A
(2014)
Peripheral blood leukocytes of cows with subclinical endometritis show an altered cellular composition and gene expression.
in Theriogenology
Carvalho AV
(2014)
SOCS genes expression during physiological and perturbed implantation in bovine endometrium.
in Reproduction (Cambridge, England)
Carneiro LC
(2016)
Mechanisms linking bacterial infections of the bovine endometrium to disease and infertility.
in Reproductive biology
Amos MR
(2014)
Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle.
in Biology of reproduction
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. I AM RESUBMITTING BECAUSE THE SYSTEM SAYS I HAVE NOT SUBMITTED THIS? |
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 | 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 | 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 |