Mechanisms of host-pathogen interaction between the bovine endometrium and the cholesterol dependent cytolysin of Trueperella pyogenes

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Mechanisms of interaction between the bovine endometrium and the cytolysin of Trueperella pyogenesDairy cows commonly suffer bacterial disease of the uterus after parturition. We will find out how the most important bacteria damage the cells of the uterus and how the cells respond. The results will direct the development of new treatments.IMPORTANCEDairy cows are important as they supply milk for human consumption. Production of milk depends on the fertility of the cow, because if there is no calf, there is no milk. Cows need to produce a calf each year to maintain milk production, so they must conceive about 3 months after calving. However, a common disease among dairy cows threatens this process. Dairy cows are particularly susceptible to infection of the uterus after calving. Every year almost half of all dairy cows develop a bacterial infection of the uterus, resulting in the discharge of copious amounts of pus from the genital tract, and causing the animal pain and suffering. The disease also reduces milk yields and causes infertility. Unfortunately, treatments have changed little in the last forty years and are not particularly effective, with many animals remaining infertile. Uterine disease costs the EU dairy industry 1.4 billion Euro each year for treatment, reduced milk yields and replacement of infertile animals. Farmers keep extra animals to replace infertile cows but these extra animals also have a damaging effect on the environment. Extra animals mean more strain on land and water resources, and increased production of greenhouse gases. So, there is an urgent need to improve the treatment of uterine disease.CONTEXTSeveral bacteria cause uterine disease, but only the presence of Trueperella pyogenes - literally "the pus producer" - is consistently associated with the severity of disease, tissue damage and infertility. There have been many clinical studies testing empirical treatments for uterine disease but with little success. Our idea is to start at the "other end" of the problem and find out the mechanisms linking Trueperella pyogenes with disease. All our strains of Trueperella pyogenes from the diseased uterus produce a toxin called pyolysin. Other disease-causing bacteria that infect different tissues in the human body produce similar toxins. These toxins are attracted to areas of cholesterol in the cell membrane where they form holes, which kills the cells. In preliminary work we have established that pyolysin also kills endometrial cells.RESEARCH AIMSOur research aims are to find out how the cells of the uterus respond to pyolysin; how sex hormones or metabolism affect the response to the toxin; and how cells detect pyolysin and defend themselves against it.THE RESEARCHFirst we will test how sensitive each of the cell types in the uterus is to pyolysin - what concentration of the toxin kills the cells and how the cells respond to lower concentrations. To aid in these experiments we have pure pyolysin, antibodies against pyolysin, and genetically manipulated on of our strains of T. pyogenes to remove the ability to produce pyolysin. We have many years of experience in collecting and using the cells from the uterus, and recently developed a new method of studying intact uterine tissue in the laboratory. To further understand the mechanisms of disease, we will work out how the hormones and metabolism that regulate endometrial function may also modify the interaction between pyolysin and cells. Finally, we will identify the mechanisms used by cells to detect or recognise pyolysin, and the ways in which they defend themselves against the toxin. We are encouraged that we can make a major step forward because, during preliminary work, we made an unexpected discovery of certain drugs that protect endometrial cells against pyolysin.IMPACT OF THE RESEARCHOur research will provide a platform for the rational design of new treatments to limit or prevent uterine disease in cattle.