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Prions and their lethal journey to the brain

Key Points

  • Many prion diseases, including variant Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy, chronic wasting disease in mule deer and elk, and scrapie in sheep and goats, are acquired by peripheral exposure such as ingestion of contaminated food. Iatrogenic transmissions have also occurred between humans.

  • After exposure, prions usually accumulate in lymphoid tissues (for example, the spleen, lymph nodes, tonsils and Peyer's patches) before they infect the brain.

  • In vitro studies suggest that both M cells and intestinal epithelial cells could transfer prions across the epithelium from the intestinal lumen.

  • Once across the intestinal epithelium, migratory bone-marrow-derived dendritic cells (DCs) are ideally situated to acquire and transport prions to lymphoid tissues. The precise involvement of DCs in pathogenesis is uncertain, but a subpopulation of DCs can acquire disease-specific prion protein (PrP) from the intestine and transport it to the mesenteric lymph nodes.

  • Macrophages also acquire prions, but these cells are unlikely to be involved in transport as they destroy them.

  • Once prions reach the lymphoid tissues, they accumulate predominantly on follicular dendritic cells (FDCs). Opsonizing complement components and cellular complement receptors appear to be important for the localization of prions to FDCs. Temporary FDC depletion blocks the accumulation of prions in lymphoid tissues and their subsequent spread to the brain.

  • Neuroinvasion from lymphoid tissues occurs along both symphathetic nerves and fibres of the vagus nerve. But how prions are passed from the FDC to peripheral nerves is not known, as physical connections between these cells have not been observed. Both cell-associated (for example, DCs) and cell-free (for example, exosomes) mechanisms have been proposed.

  • The arrival and accumulation of prions in the brain is accompanied by neurodegeneration and, ultimately, the death of the host.

Abstract

Prion diseases are neurodegenerative conditions that cause extensive damage to nerve cells within the brain and can be fatal. Some prion disease agents accumulate first in lymphoid tissues, as they make their journey from the site of infection, such as the gut, to the brain. Studies in mouse models have shown that this accumulation is obligatory for the efficient delivery of prions to the brain. Indeed, if the accumulation of prions in lymphoid tissues is blocked, disease susceptibility is reduced. Therefore, the identification of the cells and molecules that are involved in the delivery of prions to the brain might identify targets for therapeutic intervention. This review describes the current understanding of the mechanisms involved in the delivery of prions to the brain.

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Figure 1: A model of the molecular and cellular components of transmissible spongiform encephalopathy (TSE) pathogenesis in lymphoid tissues.
Figure 2: Potential mechanisms of transmissible spongiform encephalopathy (TSE) agent translocation across the intestinal epithelium.
Figure 3: Innervation of the spleen.
Figure 4: Initial pathways of transmissible spongiform encephalopathy (TSE) agent neuroinvasion from the intestine.

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Acknowledgements

We thank P. McBride (Institute of Animal Health, Edinburgh) for helpful discussion. This work is supported by grants from the Biological Sciences Research Council (UK), the Medical Research Council (UK) and the European Commission. N.A.M and G.G.Mc.P. are collaborators in a consortium of 7 EU laboratories funded by the European Commision.

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FURTHER INFORMATION

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Gordon MacPherson's homepage

Scottish TSE Network

UK Creutzfeldt-Jakob disease Surveillance Unit

The inquiry into BSE and vCJD in the United Kingdom

Chronic wasting disease alliance

Immuno TSE

NeuroPrion: a network of excellence on prion diseases

Glossary

Peyer's patches

Specialized lymphoid follicles localized in the submucosa of the small intestine. They contain B-cell follicles and interfollicular T-cell areas, with an outer epithelial layer containing specialized epithelial cells called microfold (M) cells.

Gut-associated lymphoid tissues

(GALT). Secondary lymphoid tissues associated with the gastrointestinal tract including the Peyer's patches, tonsils, mesenteric lymph nodes and the appendix.

Mesenteric lymph nodes

Lymph nodes located along the mesenteric artery in the mesenteries between intestinal loops. They receive lymph from the lymphatic vessels that drain the intestine.

Germinal centre

A structure that is found in the follicles of secondary lymphoid tissues (the spleen, Peyer's patches and lymph nodes) composed of proliferating B cells.

B-cell follicle

An aggregate of B cells in lymphoid tissues that contains naive B cells, as well as activated, proliferating and maturating B cells in germinal centres.

Follicular dendritic cells

Specialized non-haematopoietic stromal cells that reside in the follicles and germinal centres. These cells possess long dendrites and carry intact antigen in immune complexes on their surface.

Complement

A part of the innate immune system comprising serum proteins that can protect against infection.

Tight junction

A region of apical adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux and contribute to the maintenance of cell polarity by stopping molecules from diffusing in the plane of the membrane.

Follicle-associated epithelium

The epithelium that overlies mucosal lymphoid tissues, such as the Peyer's patches, and which is specialized in antigen capture and transport.

Afferent lymphatics

Vessels that drain extracellular fluid (lymph) from the tissues to lymph nodes. They can also contain antigens and antigen-bearing dendritic cells and macrophages from infected tissues.

Efferent mesenteric lymphatics

Vessels that carry lymph and antigen-specific lymphocytes from the lymph node.

Autonomic nervous system

The part of the nervous system that is not under conscious control and regulates functions such as breathing, circulation and digestion. The autonomic nervous system has two subdivisions: the sympathetic nervous system and the parasympathetic nervous system.

Sympathetic nerve

These nerves originate in the thoracic regions of the spinal cord. Their stimulation reverses the effects of the parasympathetic nervous system, for example, reduces digestive secretion, increases heart-rate and constricts blood vessels.

Parasympathetic nerve

These nerves originate in the brain stem and lower part of the spinal cord. Their stimulation reverses the effects of the sympathetic nervous system, for example, stimulates digestive secretion, decreases heart-rate, dilates blood vessels and relaxes sphincter muscles.

Splanchnic nerve

The major nerve supplying sympathetic innervation to the organs in the abdominal cavity.

Vagus nerve

Component of the parasympathetic nervous system. Tenth pair of cranial nerves, originates in medulla oblongata of brain stem and supplies the pharynx, larynx, lungs, heart, oesophagus, stomach and most of the abdominal viscera.

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Mabbott, N., MacPherson, G. Prions and their lethal journey to the brain. Nat Rev Microbiol 4, 201–211 (2006). https://doi.org/10.1038/nrmicro1346

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