Prions in the Gut: Dietary Proteins or Infectious Pathogens?

How do orally ingested infectious prions find their way to the brain? An article by Ricki Lewis in this issue of The Scientist (See "Portals for Prions?") describes recent hypotheses about trafficking of prions from gastrointestinal tract via lymphoid cells to the central nervous system. The most attractive point of entry for the ingested prions seems to be directly in the gut, where contaminated food is first deposited. Gastroenterologists have long known about the specialized subpopulation of enterocytes, m cells, whose function is to sample gut antigens and to pass them on for inspection to the immune system.1 m cells are embedded in gut epithelial surfaces, where they overlay mucosal lymphoid tissues populated by T cells, B cells and various antigen presenting cells (APC) including dendritic cells (DC) and macrophages. Recent studies suggest that m cells do not break down orally administered antigens; this function, and the subsequent presentation of processed antigens to T cells, is carried out by bone marrow-derived APC, probably DC.2 Precursors of m cells, enterocytes (EC), are also implicated in transcytosis of some intact particles and, indirectly, in presentation of processed antigens to T cells. What happens to antigens that pass the intestinal transepithelial barrier? Intact macromolecules, including dietary proteins, can be found in blood, suggesting existence of a direct pathway for circulating undigested, gut-derived proteins into remote tissues. More interesting is the fate of antigens entering mucosal immune tissue. It is here that the immune system starts to sort out the antigens into harmless dietary proteins that need to be tolerated, and potentially dangerous pathogens that must be met with an effective immune response to prevent the spread of infection to other organs. The key cells that are suspected to control tolerance and immunity are antigen processing and presenting DC and EC, that can be engulfed by DC.2 Different subsets of DC induce different long-term responses and the type of DC called into action depends on microenvironmental milieu that arises in mucosa upon entry of the antigen into the gut. Most pathogens raise a red flag and shape their environment immediately after entering the digestive tract. They contain uncommon biochemical components, usually foreign to mammals, such as sugar and glycolipid constituents of bacterial cell walls, double stranded viral RNA, bacterial CpG DNA. Presence of these compounds awakens host innate responses to signal danger via cytokines and other mediators of inflammation. Dietary proteins, in contrast, fail to produce danger signals and do not program immune DC to sensitize T and B cells for a long term adaptive immune response. Instead, dietary proteins are processed by different DC subsets that induce tolerance.2 Infectious prion units contain aggregates of Prion Protein Scrapie (PrPSc)-like prions and are simply misfolded mammalian proteins.3 If this is all they really are, they appear to the gut immune system like any other dietary antigen, which may differ in the amino acid sequence from the host proteins, but are unable to jump-start the adaptive immune response. Furthermore, infectious prions seem to have no prior knowledge of gut environment, since they derive from normal prion protein that was misfolded in the brain of their previous host. Seasoned gut pathogens, on the other hand, continuously undergo mutation/selection to enhance their chances of productive infection and survival in the face of an active host immune system. Thus, if intact prions enter the bloodstream and DC via m cells and/or other transcytosing EC, it is because these pathways allow many undigested macromolecules to gain access to the host, and not because prions have subverted m cells to serve their infectious purpose. This passive entry may be quite sufficient for a prion to embark on its fatal journey into the host's brain. However, for immunologists who work on orally transmitted diseases, it is a relief that prions can be envisioned as insidious toxic foodstuff, rather than subversive and evolving infectious pathogens of the gastrointestinal tract. Iwona Stroynowski (stroynow@utsw.swmed.edu) is an associate professor in the Center for Immunology at the University of Texas Southwestern Medical School in Dallas. References 1. J.-P. Kraehenbuhl and M.R. Neutra, "Epithelial M cells: differentiation and function," Annual Review of Cell and Developmental Biology, 16:301-32, 2000. 2. C. Nagler-Anderson et al., "Mucosal antigen presentation and the control of tolerance and immunity," Trends in Immunology, 22[3]:120-2, March 2001. 3. S.B. Prusiner, "Prions," Proceedings of the National Academy of Science, 95:13363-83, 1998.

Prions in the Gut: Dietary Proteins or Infectious Pathogens?

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