The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Critical Role in Oral Prion Disease Pathogenesis

Gut associated lymphoid tissue (GALT) is present throughout the small and large intestines (SI and LI), consisting of multi-follicular Peyer’s patches (and equivalents in the caecum and colon) and solitary isolated lymphoid tissue.  Determining the contribution of GALT in the SI and LI in diseases not confined to particular intestinal niches remains problematic as manipulations to alter GALT generally affect GALT in both the SI and LI. Oral infection with prion disease requires GALT, primarily for transport through M cells and replication within B cell follicles. Detection of prions within LI GALT has been suggested as a diagnostic in humans and animals, however whether this is a primary site of infection was unknown. Using a novel model in which mice lacked SI GALT, we have shown that an absence of SI GALT dramatically reduces susceptibility to oral prion infection.  Additionally, co-infection with a LI restricted pathogen (Trichuris muris) did not alter prion disease susceptibility.  Therefore, following oral exposure, the initial prion infection is restricted to SI GALT.  Furthermore, these data suggest that whilst SI and LI GALT are similar, LI GALT is relatively deficient in the uptake of non-motile pathogens from the lumen.