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  • Review Article
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Pathogenesis of prion diseases: current status and future outlook

Nature Reviews Microbiology volume 4, pages 765–775 (2006)Cite this article

Key Points

  • Prion diseases are progressive, transmissible neurodegenerative disorders with an invariably fatal outcome. Prions, the infectious agent of prion diseases, accumulate in the central nervous system, in organs of the secondary lymphoid system and in blood.

  • Examples of prion diseases include bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep and goat, chronic wasting disease in deer and elk, and sporadic and variant Creutzfeldt–Jakob disease in humans.

  • Neuronal cytotoxicity of PrPSc depends on the expression of PrPC. Evidence indicates that the conversion of PrPC to PrPSc is deleterious, but the mechanisms of neural degeneration are still unclear.

  • In this article, we describe the role of the immune system in prion diseases and review our current understanding of cellular and molecular mechanisms involved in peripheral prion replication and transport.

  • Several prion diseases are transmitted by peripheral prion uptake (for example, ingestion of prion-contaminated food). After prion uptake, a replication phase occurs in lymphoid tissue before neuroinvasion.

  • In the peripheral regions of the host, the abnormally folded, aggregated PrPSc, is amplified by cells of the immune system (for example, follicular dendritic cells) in the germinal centres, located in B-cell follicles of the spleen or lymph nodes.

  • Depletion of mature follicular dendritic cells delays the development of prion disease following intraperitoneal inoculation. This could form the basis of a post-exposure prophylactic strategy.

  • Recent findings indicate that chronic inflammation can induce the deposition of prion infectivity in organs previously believed to be prion free.

Abstract

The prion, a conformational variant of a host protein, is the infectious particle responsible for transmissible spongiform encephalopathy (TSE), a fatal neurodegenerative disease of humans and animals. The principal target of prion pathology is the brain, yet most TSEs also display prion replication at extra-cerebral locations, including secondary lymphoid organs and sites of chronic inflammation. Despite significant progress in our understanding of this infectious agent, many fundamental questions relating to the nature of the prion, including the mechanism of replication and the molecular events underlying brain damage, remain unanswered. Here we focus on the unresolved issues pertaining to prion pathogenesis, particularly on the role played by the immune system.

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Figure 1: Human tissues and blood involved in propagation and transport of prions.
Figure 2: Structural features of the cellular prion protein.
Figure 3: PrPSc and prion infectivity in chronically inflamed murine or ovine tissue.
Figure 4: Induction of tertiary follicles and prion replication competence in non-lymphoid tissue.

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Acknowledgements

We thank F. Baumann, C. Sigurdson and A. Schumacher for their active discussions and critical reading of this review. A. A. is supported by grants from the EU, the Swiss National Foundation, the National Centre of Competence in Research on Neural Plasticity and Repair, the Stammbach Foundation and the Ernst-Jung Foundation. M.H. is supported by the Foundation for Research at the Medical Faculty, University of Zurich, the Bonizzi-Theler Stiftung and by the Verein zur Förderung des akademischen Nachwuchses (FAN).

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  1. Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, Zürich, CH-8091, Switzerland

    Adriano Aguzzi & Mathias Heikenwalder

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  1. Adriano Aguzzi
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Correspondence to Adriano Aguzzi.

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DATABASES

UniProtKB

MyD88

FURTHER INFORMATION

Institute of Neuropathology

Glossary

Iatrogenic transmission

The transmission of infectious agents as a consequence of a medical procedure.

Lymphoreticular system

The lymphoreticular system (LRS) is divided into primary and secondary lymphoid tissues. Primary lymphoid organs are anatomical sites where the cells of the LRS are generated, including the bone marrow and the thymus. Secondary lymphoid organs are sites where the LRS cells function. These sites include the spleen, the lymph nodes and mucosa associated lymphoid tissue. Tertiary lymphoid organs arise at sites of chronic inflammation.

Peripheral prion inoculation

This defines any administration of the prion agent other than into the central nervous system, including intraperitoneal (ip), intravenous (iv), oral or intraocular (io) administration.

Splenic stroma

The splenic stroma defines those cells in the spleen, which are of non-hematopoietic origin and are resistant to γ-irradiation.

Splenic pulp

The splenic pulp can be subdivided into the red and the white splenic pulp. The splenic red pulp fills the sinuses of the spleen and its composition includes macrophages and red blood cells. The white splenic pulp is a parenchymatous tissue of the spleen consisting of compact masses of lymphatic cells and contains the germinal centres.

Homeostatic chemokine

A subset of the chemokine family that are constitutively expressed in pre-formed lymphoid tissues and which promote and maintain the organization of this tissue.

FDC-M1 positive cluster

A dense network of cells found in germinal centres, immunoreactive for the FDC-M1 antibody and the CD21/35 receptor. Tingible body macrophages also stain positive for FDC-M1 but are morphologically distinct.

Lymphotoxin

(LT). LTα and LTβ are proinflammatory cytokines that belong to the tumour necrosis factor (TNF) superfamily. They are mainly expressed by B- and T lymphocytes, and natural killer cells. LTs exist as membrane-bound heterotrimers (LTα1β2 or LTα2β1) or as secreted homotrimers (LTα3). LTs bind TNFR1 or LTβR inducing a signalling cascade that is important for the maturation and maintenance of follicular dendritic cells.

Ectopic expression

This defines the expression of a gene in an abnormal site in an organism. This phenomenon can be induced by disease or by a pathogen, but can be also induced artificially by expressing a transgene with a tissue or cell-specific promoter.

LTβR pathway

Following interaction with lymphotoxin ligands, LTβR can activate an 'alternative' pathway for NFκB, inducing the expression of genes such as homeostatic chemokines and tumour necrosis superfamily members, which is important for the maintenance and maturation of follicular dendritic cells.

Extra-neural compartment

This includes organs and cells that do not belong to the central or peripheral nervous system.

Innervation pattern

This describes the type (qualitative and quantitative) of innervation present in a peripheral organ that does not belong to the central nervous system.

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Aguzzi, A., Heikenwalder, M. Pathogenesis of prion diseases: current status and future outlook. Nat Rev Microbiol 4, 765–775 (2006). https://doi.org/10.1038/nrmicro1492

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