Oral prion infection requires normal numbers of Peyer's patches but not of enteric lymphocytes

Prion pathogenesis following oral exposure is thought to involve gut-associated lymphatic tissue, which includes Peyer's patches (PPs) and M cells. Recruitment of activated B lymphocytes to PPs requires alpha(4)beta(7) integrin; PPs of beta7(-/-) mice are normal in number but are atrophic and almost entirely devoid of B cells. Here we report that minimal infectious dose and disease incubation after oral exposure to logarithmic dilutions of prion inoculum were similar in beta7(-/-) and wild-type mice, and PPs of both beta7(-/-) and wild-type mice contained 3-4 log LD50/g prion infectivity greater than or equal to125 days after challenge. Despite marked reduction of B cells, M cells were present in beta7(-/-) mice. In contrast, mice deficient in both tumor necrosis factor and lymphotoxin-alpha (TNFalpha(-/-) x LTalpha(-/-)) or in lymphocytes (RAG-1(-/-), muMT), in which numbers of PPs are reduced in number, were highly resistant to oral challenge, and their intestines were virtually devoid of prion infectivity at all times after challenge. Therefore, lymphoreticular requirements for enteric and for intraperitoneal uptake of prions differ from each other. Although susceptibility to prion infection following oral challenge correlates with the number of PPs, it is remarkably independent of the number of PP-associated lymphocytes.