The gut-associated lymphoid tissues in the small intestine, not the large intestine, play a major role in oral prion disease pathogenesis

David Donaldson, Kathryn J. Else, Neil Mabbott

Research output: Contribution to journalArticlepeer-review

Abstract

Prion diseases are infectious neurodegenerative disorders characterised by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally and following exposure the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsies has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk to infection and the pre-clinical diagnosis of disease.
Original languageEnglish
Pages (from-to)9532-9547
JournalJournal of Virology
Volume89
Issue number18
Early online date8 Jul 2015
DOIs
Publication statusPublished - Sep 2015

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