The influence of the GALT in TSE agent neuroinvasion from the large intestine

Transmissible spongiform encephalophathies (TSEs) are prolonged diseases which cause extensive damage to nerves in the brain. In the absence of a cure TSE diseases are invariably fatal. These diseases affect both animals and humans, and include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in mule deer and elk, and scrapie in sheep and goats. Some animal species and humans have become infected with these diseases after eating TSE agent-contaminated food, or through transplantation of TSE agent-contaminated tissues or tissue products (eg: transfusion of blood from a variant CJD-infected donor). Many questions remain concerning the route the infectious TSE agent takes from the site of exposure (eg: intestine) to the brain where it causes damage to nerve cells. We have shown that soon after exposure TSE agents first target and accumulate within lymphoid tissues (Peyer's patches in the small intestine, lymph nodes and spleen) before they spread to the brain. Many TSE agents must accumulate in these lymphoid tissues before they can subsequently spread to the brain (a process termed neuroinvasion) where they ultimately cause neurodegeneration and death. After oral exposure TSE agents also accumulate within lymphoid tissues in the large intestine such as the appendix. However, the contribution of the large intestine to oral TSE pathogenesis is unknown and has been mostly overlooked. This is unfortunate as the large intestine may be an important early site of TSE agent accumulation that influences disease susceptibility. For example, inflammation or pathology within the large intestine may affect disease susceptibility. In the current project, mice will be created that contain lymphoid tissues in the large intestine only. These mice will be used to test the hypothesis that lymphoid tissues in the large intestine are important sites of TSE agent accumulation which influence disease pathogenesis and susceptibility. To achieve this, the following measurable objectives will be addressed: Objective 1- Characterise the development and status of the lymphoid tissues within the small and large intestines Objective 2- Determine the influence of lymphoid tissues in TSE agent neuroinvasion from the large intestine Finally, the effects that other intestinal pathogens may have on TSE susceptibility are not known. For example, the pathology that these pathogens cause in the intestine may increase the uptake of the TSE agent, whereas an influx of inflammatory cells may destroy the TSE agent reducing susceptibility. In Objective 3 the effects of infection with a common gut parasite on oral TSE pathogenesis will be determined. These data will provide predictions on how infection with gastrointestinal pathogens may influence TSE susceptibility. Objective 3- Determine the influence of infection with a gastrointestinal pathogen on oral TSE pathogenesis Currently, effective therapeutics and prophylactics to treat TSE diseases are lacking. Furthermore, no reliable preclinical diagnostic test is available. A thorough understanding of the early events in TSE pathogenesis will aid the determination of risk, the development of pre-clinical diagnostics and therapeutics, especially the development TSE-specific mucosal vaccines.

After oral exposure transmissible spongiform encephalopathy (TSE) agent accumulation in the gut-associated lymphoid tissues (GALT), especially Peyer's patches and isolated lymphoid follicles in the small intestine, is critical for the spread of disease to the brain. Many TSE agents also accumulate within GALT in the large intestine such as the appendix and rectal-associated lymphoid follicles, but the influence this has on pathogenesis is unknown. The large intestine GALT may be important early sites of TSE agent accumulation that influence disease susceptibility. Here, mice will be created that contain large intestine GALT only. Transient in utero lymphotoxin-blockade blocks Peyer's patch, colonic patch and lymph node formation, but stimulates the post-natal development of isolated lymphoid follicles throughout the intestine. Interestingly, large intestine isolated lymphoid follicles develop several weeks before those in the small intestine. These characteristics will be used to create mice that contain large intestine GALT only (large intestine-isolated lymphoid follicles) at the time of oral TSE agent exposure. These mice will be used to test the hypothesis that the large intestine GALT is also an important site of TSE agent accumulation and neuroinvasion. To do so, the following objectives will be addressed: Objective 1- Characterise the development and status of the GALT in the small and large intestines during the first few weeks of development Objective 2- Determine the influence of the GALT in TSE agent neuroinvasion from the large intestine Objective 3- Determine the influence of infection with a gastrointestinal pathogen on oral TSE pathogenesis This experiment will provide predictions on how infection with other gut pathogens may affect TSE pathogenesis. A thorough understanding of the early events in TSE pathogenesis will aid the determination of risk, the development of pre-clinical diagnostics and therapeutics, especially mucosal vaccines.