Study Reveals How Prion Diseases Spread From the Gut to the Brain

Diagnosis of deadly brain conditions could be helped by new research that shows how infectious proteins that cause the disease spread.

The study reveals how the proteins, called prions, spread from the gut to the brain after a person or animal has eaten contaminated meat.

Scientists say their findings could aid the earlier diagnosis of prion diseases – which include variant Creutzfeldt-Jakob disease (vCJD) in people and bovine spongiform encephalopathy (BSE) in cows.

In people, the disease remains very rare, 229 people have died from vCJD since it was first identified almost 20 years ago, of which 177 were from the UK.

Prions are infectious proteins with abnormal shapes that can be passed between people and animals by eating contaminated meat. Until now, it was not known how prions spread from the gut to the brain after consuming infected meat.

Researchers at University of Edinburgh’s Roslin Institute studied the course of prion infection in mice.

They found that prions must first build up in specialised structures in the lining of the small intestine before they are able to spread throughout the body to the brain.

The structures – called Peyer’s patches – are part of the body’s immune system and form the first line of defence against contaminated food. The study suggests prions hijack Peyer’s patches to cause infection.

Prions did not build up in similar patches in the large intestine until a later stage of infection, the team found. At this stage, prions were also detected in the spleen and lymph nodes.

As many as one in 2000 people in the UK could be carrying infectious prions without showing any symptoms of disease, according to recent estimates. These are based on analysis of tissue taken during routine appendix removal operations.

This shows Peyer's patches in the small intestine.
This magnified image of the small intestine shows specialized structures called Peyer’s patches, which are part of the body’s immune system. Researchers have shown how deadly proteins called prions, which cause variant CJD in people and BSE in cows, invade the body through Peyer’s patches before infecting the brain. Image credit: Prof. Neil Mabbott & Dr David Donaldson, The Roslin Institute, University of Edinburgh.

The researchers say that these estimates may fail to identify individuals in the earliest stages of infection, where prions have not yet spread beyond the small intestine.

When prions get into the brain, they destroy nerve cells. This can lead to major neurological symptoms including memory impairment, personality changes, and difficulties with movement.

Other prion diseases include scrapie in sheep and chronic wasting disease in deer.

Professor Neil Mabbott, of The Roslin Institute at the University of Edinburgh, who led the study, said: “Whether all individuals with evidence of prion infection in their gut go on to develop neurological disease is not known. We need a greater understanding of what factors enhance our susceptibility to prion diseases so that we can put in place safeguards to prevent these conditions from spreading in people and farmed animals.”

About this neurology research

Funding: The study was funded by the Biotechnology and Biological Sciences Research Council.

Source: Jen Middleton – University of Edinburgh
Image Credit: The image is credited to Prof. Neil Mabbott & Dr. David Donaldson, The Roslin Institute, University of Edinburgh
Original Research: Abstract for “The gut-associated lymphoid tissues in the small intestine, not the large intestine, play a major role in oral prion disease pathogenesis” by David S. Donaldson, Kathryn J. Else, and Neil A. Mabbott in Journal of Virology. Published online July 8 2015 doi:10.1128/JVI.01544-15


Abstract

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

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.

“The gut-associated lymphoid tissues in the small intestine, not the large intestine, play a major role in oral prion disease pathogenesis” by David S. Donaldson, Kathryn J. Else, and Neil A. Mabbott in Journal of Virology. Published online July 8 2015 doi:10.1128/JVI.01544-15

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