Mechanisms linking bacterial infections of the bovine endometrium to disease and infertility

Bacterial infections of the endometrium after parturition commonly cause metritis and endometritis in dairy cattle, and these diseases are important because they compromise animal welfare and incur economic costs, as well as delaying or preventing conception. Here we highlight that uterine infections cause infertility, discuss which bacteria cause uterine disease, and review the evidence for mechanisms of inflammation and tissue damage in the endometrium. Bacteria cultured from the uterus of diseased animals include Escherichia coli, Trueperella pyogenes, and several anaerobic species, but their causative role in disease is challenged by the discovery of many other bacteria in the uterine disease microbiome. Irrespective of the species of bacteria, endometrial cell inflammatory responses to infection initially depend on innate immunity, with Toll-like receptors binding pathogen-associated molecular patterns, such as lipopolysaccharide and bacterial lipopeptides. In addition to tissue damage associated with parturition and inflammation, endometrial cell death is caused by a cholesterol-dependent cytolysin secreted by T. pyogenes, called pyolysin, which forms pores in plasma membranes of endometrial cells. However, endometrial cells surprisingly do not sense damage-associated molecular patterns, but a combination of infections followed by cell damage leads to release of the intracellular cytokine interleukin (IL)-1 alpha from endometrial cells, which then acts to scale inflammatory responses. To develop strategies to limit the impact of uterine disease on fertility, future work should focus on determining which bacteria and virulence factors cause endometritis, and understanding how the host response to infection is regulated in the endometrium.