Mevalonate Biosynthesis Intermediates Are Key Regulators of Innate Immunity in Bovine Endometritis

Metabolic changes can influence inflammatory responses to bacteria. To examine whether localized manipulation of the mevalonate pathway impacts innate immunity, we exploited a unique mucosal disease model, endometritis, where inflammation is a consequence of innate immunity. IL responses to pathogenic bacteria and LPS were modulated in bovine endometrial cell and organ cultures by small molecules that target the mevalonate pathway. Treatment with multiple statins, bisphosphonates, squalene synthase inhibitors, and small interfering RNA showed that inhibition of farnesyl-diphosphate farnesyl transferase (squalene synthase), but not 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyl diphosphate synthase, reduced endometrial organ and cellular inflammatory responses to pathogenic bacteria and LPS. Although manipulation of the mevalonate pathway reduced cellular cholesterol, impacts on inflammation were independent of cholesterol concentration as cholesterol depletion using cyclodextrins did not alter inflammatory responses. Treatment with the isoprenoid mevalonate pathway-intermediates, farnesyl diphosphate and geranylgeranyl diphosphate, also reduced endometrial cellular inflammatory responses to LPS. These data imply that manipulating the mevalonate pathway regulates innate immunity within the endometrium, and that isoprenoids are regulatory molecules in this process, knowledge that could be exploited for novel therapeutic strategies

United against rabies forum:The one health concept at work

Human deaths from rabies are preventable and can be eliminated by applying a systematic One Health approach. However, this ancient disease still threatens the lives of millions of people in up to 150 countries and kills an estimated 59, 000 people every year. Rabies today is largely a disease of poverty, almost always linked to dog bites, with most deaths occurring in neglected communities in Africa and Asia. The disease places an immense economic burden on its victims, a cost that far outweighs the investment needed to control it. A global framework for rabies elimination in humans is set out in Zero by 30: The Global Strategic Plan to end human deaths from dog-mediated rabies by 2030. Despite the existence of proven control strategies and agreement on the path to eliminating human rabies deaths, mortality numbers from rabies remain high, and COVID-19 has set back efforts even further. But COVID-19 has also highlighted the value of a One Health approach to zoonotic disease and pandemic prevention. Rabies control programs offer a practical route to building One Health capacities that can also address other zoonotic threats, including those with pandemic potential. The United Against Rabies Forum aims to accelerate progress on rabies elimination while applying a One Health approach. The Forum promotes cross-sector collaboration among stakeholders and supports countries in their rabies elimination efforts. Increased political engagement and resource mobilization, both internationally and nationally, will be needed to achieve global rabies goals and can also make One Health implementation a reality

Subclinical endometritis in dairy cattle is associated with distinct mRNA expression patterns in blood and endometrium

Cattle with subclinical endometritis (SCE) are sub-fertile and diagnosing subclinical uterine disease remains a challenge. The hypothesis for this study was that endometrial inflammation is reflected in mRNA expression patterns of peripheral blood leucocytes. Transcriptome profiles were evaluated in healthy cows and in cows with SCE using circulating white blood cells (WBC) and endometrial biopsy samples collected from the same animals at 45–55 days postpartum. Bioinformatic analyses of microarray-based transcriptional data identified gene profiles associated with distinct biological functions in circulating WBC and endometrium. In circulating WBC, SCE promotes a pro-inflammatory environment, whereas functions related to tissue remodeling are also affected in the endometrium. Nineteen differentially expressed genes associated with SCE were common to both circulating WBC and the endometrium. Among these genes, transcript abundance of immune factors C3, C2, LTF, PF4 and TRAPPC13 were up-regulated in SCE cows at 45–55 days postpartum. Moreover, mRNA expression of C3, CXCL8, LTF, TLR2 and TRAPPC13 was temporally regulated during the postpartum period in circulating WBC of healthy cows compared with SCE cows. This observation might indicate an advantageous modulation of the immune system in healthy animals. The transcript abundance of these genes represents a potential source of indicators for postpartum uterine health

Engaging the actors to ensure impacts of public–private partnerships

Evaluation and actor engagement are essential to ensure performance and sustainability of actions implemented, especially under public–private partnerships (PPPs). In the context of the OIE PPP initiative, the OIE and CIRAD have developed a participatory evaluation method to assess the added value of PPPs in the veterinary domain

The Diversity of Impacts Brought by Sound Implementation of Public-Private Partnerships in the Veterinary Domain

Public Private Partnership (PPP) is defined as a joint approach in which the public and private sector agree responsibilities and share resources and risks to achieve common objectives that deliver benefits in a sustainable manner. However only limited information is available on the added value of PPP in the veterinary domain. The aim of this study was to identify the different benefits and impacts lead by PPPs implemented in this field. A structured questionnaire survey was implemented by the World Organisation for Animal Health (OIE) to collect data on the different types of PPPs worldwide (n=181 countries). Three case studies were selected from the survey results (n=97) for CIRAD to implement an in depth impact assessment. An expert opinion elicitation involving around 40 experts was performed using semi-structured interviews and an expert meeting in October 2018 to validate the list of benefits and impacts developed. Sixteen categories of benefits (direct effect) and five categories of impacts (long term influence) were identified: stronger national economy; greater trust in public and private partners; reduced business risk and increased opportunities; improved public health (reduced zoonotic risk and improved food security) and societal issues such as livelihood improvement and reduction in gender inequality. This study represents the first practical attempt to represent the diversity of impacts that proper implementation of PPPs in the field of veterinary domain could generate. This work is currently contributing to the development of OIE guidelines to promote good practices for impactful and sustainable PPPs in the veterinary domain

An evaluation tool to strengthen the collaborative process of the public-private partnership in the veterinary domain

International audiencePublic-private partnerships (PPPs) in the veterinary domain are widely implemented worldwide and can help to strengthen the capacities of Veterinary Services. Few analyses have been made of these initiatives. This study is aimed at developing an evaluation tool based on participatory approaches and focusing on the quality of PPP processes in the veterinary domain. The tool was divided into ten sections relevant to PPP process organisation and activities. The 44 evaluation criteria and six quality attributes (operationality, relevance, acceptability, inclusiveness, adaptability, and stability) were identified based on literature review and case-study application. The tool was adjusted during four regional PPP training workshops bringing together stakeholders from both public and private sectors. Finally, the tool was validated through an experts' elicitation process and applied in the field in Paraguay. The tool was developed in a non-normative perspective to help the partners adapt the PPP to their specific context, to maximize the opportunities and minimize the risks of such collaborations, and to formulate adapted recommendations to strengthen and improve the PPP collaborative process and thus the outcomes. In an ex-ante perspective, this tool would also help public and private actors to engage and develop a PPP process following the best possible practices. The aim of this tool is to help decision making in terms of PPP development and implementation in the veterinary domain to ensure the added value and relevance of such a collaborative approach in different countries worldwide

Typological analysis of public-private partnerships in the veterinary domain

Public-Private Partnerships (PPPs) are defined as a collaborative approach in which the public and private sector share resources, responsibilities and risks to achieve common objectives and mutual benefits in a sustainable manner. PPPs are identified as a key solution to reinforce Veterinary Services. However only limited information is available on the scope, added value and enabling factors of PPPs in this sector. The aims of this study were to develop a typology of PPPs in the veterinary field and to identify key success factors and obstacles to their implementation. A structured questionnaire was sent to all 181 World Organisation for Animal Health (OIE) Member Countries and to 47 private contacts. 36 different variables characterizing PPP initiatives were collected. 97 examples of PPPs were retrieved from 76 countries. Dimensionality reduction techniques were combined with clustering and discrimination methods to establish a typology of PPPs and to derive a set of simple rules to classify new instances of PPPs. Three clusters were identified, separated according to two main variables: the type of private partners and the type of interaction. Cluster 1, transactional PPPs, represented the traditional understanding of PPPs by Veterinary Services, initiated and funded by the public sector, giving service delivery accreditation to mostly private veterinarians; cluster 2, collaborative PPPs, included partnerships between producer associations and public Veterinary Services, driven by trade interests; cluster 3, transformational PPPs, represented joint programs initiated and funded by private companies and initially driven by business development objectives. Specific success factors and key obstacles affecting the performances and sustainability of these initiatives were identified for each cluster. This study represents the first practical attempt to develop a meaningful typology of PPPs in the field of animal health and to identify fundamental obstacles currently inhibiting the development of PPPs, and suggests ways to support national Veterinary Services in overcoming these obstacles.Public-Private Partnerships (PPPs) are defined as a collaborative approach in which the public and private sector share resources, responsibilities and risks to achieve common objectives and mutual benefits in a sustainable manner. PPPs are identified as a key solution to reinforce Veterinary Services. However only limited information is available on the scope, added value and enabling factors of PPPs in this sector. The aims of this study were to develop a typology of PPPs in the veterinary field and to identify key success factors and obstacles to their implementation. A structured questionnaire was sent to all 181 World Organisation for Animal Health (OIE) Member Countries and to 47 private contacts. 36 different variables characterizing PPP initiatives were collected. 97 examples of PPPs were retrieved from 76 countries. Dimensionality reduction techniques were combined with clustering and discrimination methods to establish a typology of PPPs and to derive a set of simple rules to classify new instances of PPPs. Three clusters were identified, separated according to two main variables: the type of private partners and the type of interaction. Cluster 1, transactional PPPs, represented the traditional understanding of PPPs by Veterinary Services, initiated and funded by the public sector, giving service delivery accreditation to mostly private veterinarians; cluster 2, collaborative PPPs, included partnerships between producer associations and public Veterinary Services, driven by trade interests; cluster 3, transformational PPPs, represented joint programs initiated and funded by private companies and initially driven by business development objectives. Specific success factors and key obstacles affecting the performances and sustainability of these initiatives were identified for each cluster. This study represents the first practical attempt to develop a meaningful typology of PPPs in the field of animal health and to identify fundamental obstacles currently inhibiting the development of PPPs, and suggests ways to support national Veterinary Services in overcoming these obstacles

Peripheral blood leukocytes of cows with subclinical endometritis show an altered cellular composition and gene expression

Subclinical endometritis (SCE) is an important postpartum disease in dairy cows, but conventional cytobrush diagnosis often gives imprecise results. The aim of this study was to analyze disease-associated changes in peripheral blood as potential diagnostic parameters. Cellular subpopulations of blood leukocytes from cows with or without SCE (45–55 days postpartum) were flow-cytometrically quantified. Gene expression of whole blood leukocytes was assessed by PAXgene analysis. Subclinical endometritis cows showed significantly higher number of blood mononuclear cells and neutrophils. Among mononuclear cells, numbers of B-cells, NK-cells, and CD172a-positive monocytes were significantly elevated. Compared with non-SCE cows, blood leukocytes of SCE cows significantly expressed higher copy numbers of CXCL8, TNF, and IL12. To test whether circulating plasma factors are responsible for these changes, leukocytes, polymorphonuclear cells, and monocyte subpopulations (classical, intermediate, nonclassical) of healthy cows were stimulated with plasma of SCE and non-SCE cows. Although gene expression of whole leukocytes and polymorphonuclear cells remained unaltered, plasma from SCE animals significantly elevated expressed messenger RNA copy numbers of CXCL8, CXCL1, and IL1B in intermediate monocytes. In conclusion, elevated number of selected mononuclear subpopulations in peripheral blood and enhanced expression of distinct genes encoding for inflammatory mediators in blood leukocytes reflect the subclinical uterine inflammatory process in cows. Whether the observed changes in the periphery of SCE cows are the consequence of the uterine inflammatory process, or whether they affect the pathogenesis of the disease is currently unknown