Emerging Chlamydia-like organisms as novel causes of bovine reproductive failure

Many infectious diseases affect livestock, impacting not only on the health and welfare of the animals but also on the economic sustainability of the agricultural industry and future food security. Reproductive failure in cattle is one area of great concern to the agricultural sector, as it has a major impact on productivity in UK cattle herds. While there are many factors contributing to reduced rates of reproduction in livestock systems, infection plays a key role, with 77% of diagnosed cases of bovine fetal death reported as resulting from infectious causes. However, diagnosis of the infectious causes of pre-natal death in cattle is poor, with 80% of cases remaining undiagnosed (according to DEFRA's Veterinary Investigation Surveillance reports for 2002-09). This can be explained in part by a failure to detect the presence of other unidentified disease causing organisms.

In recent years, there has been an increase in the identification of a group of new emerging bacterial organisms that are found in the environment and have been shown to be associated with a variety of conditions in humans, such as pneumonia and miscarriage. These organisms, which share similar biological characteristics to Chlamydia species that are known to cause a broad range of infections in humans and animals, such as sexually-transmitted infections, pneumonia, blindness and fetal death, are referred to as Chlamydia-like organisms. These Chlamydia-like organisms are also increasingly becoming recognized as potential disease causing organisms of livestock, being particularly associated with the pre-natal death of calves. Indeed, they have been found in over a quarter of the cases analyzed in the UK, and thus could account for some of the 80% unaccounted, undiagnosed cases reported by DEFRA.

To date, the only studies that have been carried out have relied upon the analysis of tissue samples, which have been submitted to veterinary laboratories for disease diagnosis. While these studies have been vital in demonstrating the presence of the organisms in samples for which no alternative diagnoses could be reached, they have been performed on a relatively small number of samples. In addition, in general, little information is obtained on the disease and production histories of the farms from which the animals originated. Thus, this study aims to investigate the presence of these organisms on dairy farms across the UK and how this relates to animal production performance. We will isolate the organisms from clinical samples to allow us to characterise and assess how many different types of Chlamydia-like organisms are present in the UK cattle herds, as well as investigate their potential spread from animal to animal by analyzing environmental samples, such as drinking water and bedding. We will also develop experimental model systems to allow us to investigate how the organisms cause infection and disease, and determine the immune response to infection.

The combination of these studies will greatly increase our understanding of the disease causing potential and role of this group of emerging bacteria in cattle reproduction. The outcomes will lead to improved diagnoses of cattle reproductive failure, inform and educate the industry to the presence of these organisms, lead to improved management systems and allow an evaluation of the potential benefits of future vaccine strategies to prevent disease incidence.

Incidents of bovine reproductive failure have been linked to Chlamydia-like organisms, a phylogenetically diverse group of emerging pathogens that have been detected by PCR and immunohistochemistry in aborted tissues with associated histopathology. As amoebal endosymbionts, Chlamydia-like organisms can persist in the environment, however, the disease incidence, immunopathogenesis and risk factors associated with infection are unknown.

Epidemiological surveys of the incidence of Chlamydia-like organisms and other infectious abortifacients will be performed to identify risk factors associated with reproductive failure. The role of Chlamydia-like organisms in reproductive failure will be specifically investigated in a cohort study, where immunohistochemistry and histopathology will be performed on tissue samples to investigate lesion development, localise pathogens and determine a causal role in disease pathogenesis. The phylogenetic similarity of Chlamydia-like organisms detected in environmental and tissue samples will be determined to identify genotypes linked to reproductive failure and potential environmental sources of transmission. The organisms will be isolated in amoebal co-culture and phenotypically characterised. They will be used in in vitro models of placental infection to study cytokine and cellular responses to infection. An in vivo pathogenesis model will be established to study the immunological and serological responses to infection, to define the pathologies associated with infection and determine a causal role in reproductive failure.

This project will determine the prevalence of bovine reproductive failure linked to Chlamydia-like organisms in the UK, identify genotypes implicated in the disease and define immunopathology associated with infection. This will substantially advance the understanding of these emerging pathogens and make a significant contribution to the development of detection, prevention and disease management strategies.

Poor reproductive performance in cattle is of economic and welfare importance to the agricultural industry in the UK and worldwide. This project aims to generate knowledge about a group of emerging organisms that have been found to be associated with reproductive failure in cattle. In the process of this work we will analyse the impact of these organisms on cattle reproductive performance across the dairy industry, environmental contamination and provide evidence for a direct causal link between these organisms and abortion.

There will be multiple beneficiaries to the proposed work. Potential stakeholders include research scientists both national and international, academic and government research organisations, farmers, veterinary diagnostic agencies, the animal health industry and government. Ultimately the general public will benefit through improved animal health and welfare, animal production, as well as food security and safety.

This project will improve knowledge on the important abortifacients of cattle in the UK and will provide insight into the causal role of Chlamydia-like organisms on bovine reproductive failure, including information on the diversity and characterisation of the organisms and the development of in vivo model systems. The knowledge gained will open up pathways to impact at the farm level through improved farm management strategies and more effective diagnosis of cases of bovine abortion. Diagnostic tools and future vaccine development are the major potential benefits for the animal health industry, in particular farmers, veterinarians, other animal practitioners and commercial organisations. The outcomes of this research will be of interest to the farming industry, as well as government policy makers, allowing them to prioritise the management of important production diseases that impact negatively on the sustainability of the cattle industry and thus on the future security of our food. The wider public will not only benefit from this research though improved production, but there will also be a better understanding of the occurrence and role of these potentially zoonotic pathogens. The production of healthier animals, free of potential zoonotic infections will clearly benefit the public through a reduction in the possible zoonotic transmission to humans.

Knowledge exchange and outreach are important activities for communication and promotion of scientific outputs to a variety of audiences. For the scientific community this involves presentations at national and international meetings, and the production of peer reviewed publications in international journals. Communication with non-academic and non-research stakeholders will include articles for the farming and veterinary press, public engagement at science events, agricultural shows and liaising with government policy makers and potential industrial partners. We will engage and communicate with stakeholders to maximise the global impact of the proposed research. The industrial partner Pfizer will provide expertise in enhancing the outreach and impact of the project to the veterinary practitioners and will advise on possible commercial opportunities arising from the results of the project. The interaction of DairyCo whose mission statement is to 'promote world class knowledge to British dairy farmers so they can profit from a sustainable future' will further aid in the dissemination of project outputs to the agricultural community.

All the investigators have contacts and experience in these areas, providing an opportunity to promote the importance of this project. Staff working on the project will gain transferable scientific skills and will be given training that meets their personal and professional developmental needs. Transferable skills will include presentations and writing for communication with academic and non-academic audiences, time-management and project-management.