Determining the role of M cells in TSE agent neuroinvasion from the intestine

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Transmissible spongiform encephalophathies (TSEs) are prolonged diseases which cause extensive degeneration in the brain. In the absence of a cure these 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 lesions or cuts to the skin, mucous membranes or cornea. Many questions remain concerning the route the infectious TSE agent takes from the site of exposure (eg: skin lesions) to the brain where it causes damage to nerve cells. After exposure TSE agents appear to high-jack the immune system where they replicate in it before they then spread to the brain. This replication in the immune system is crucial for TSE agents to efficiently reach the brain where they ultimately cause nerve damage and death of the host. Our studies show that after oral infection TSE agents target the Peyer's patches within the intestine and infect specialised cells, termed follicular dendritic cells. During TSE disease the body is unable to recognise and destroy the TSE agents. Instead, the follicular dendritic cells become infected with high levels of TSE agents. Our research shows that the infection of follicular dendritic cells by TSE agents is a crucial early step in the disease process as treatments that block TSE infection of follicular dendritic cells, block disease transmission. How TSE agents initially infect Peyer's patches and the follicular dendritic cells within them is unknown. If we can discover how TSE agents infect these sites, we may be able to design treatments that block this ability and therefore prevent infection. The lining of the intestine is designed to prevent pathogenic microorganisms infecting the host. However, within it are specialised cells termed M cells which enable the immune system to sample the gut contents and mount an immune response if necessary. While M cells are an important component of the intestinal immune system they may also be an Achilles heal as some pathogens appear to exploit them to enter the host. Indeed some pathogens such as Salmonella may use M cells as Trojan horses to enter the body. This study will test the hypothesis that TSE agents likewise exploit M cells to gain access to Peyer's patches and infect follicular dendritic cells. If we can identify the cellular route through which TSE agents infect the host it may be possible to design treatments that block disease transmission. Currently, effective therapeutics and prophylactics to treat TSE diseases are lacking. Furthermore, no reliable preclinical diagnostic test is available. Thus 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 vaccines against TSE agents.