Prion Disease and the Innate Immune System

[lansbergen]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528271/

Viruses. 2012 December; 4(12): 3389–3419.
Published online 2012 November 28. doi: 10.3390/v4123389
Prion Disease and the Innate Immune System

Barry M. Bradford and Neil A. Mabbott*
Abstract

Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis.

 

[Sushi]

lansbergen

There are prion disorders that are found in about 20% (data not published--physician estimates) of ME patients though not the type mentioned above. This can be tested for with a PrPc functional test and this type of "misfolding" does respond to treatment.

Sushi

 

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I am following him for years and I watched the presentation in dutch.

The more severe symptoms the lower the function. Right?

I am waiting for the results to be published.

 

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http://cdmrp.army.mil/prevfunded/nprp/pbks/nprppbk.pdf

Dr. Laura Manuelidis of Yale University has focused on identifying patterns of gene expression caused by CJD infection rather than on PrP misfolding that occurs late in disease. Myeloid microglia purified from the brains of mice experimentally infected by intracerebral inoculation with CJD were first used to identify a set of genes that showed increased expression (upregulation) versus controls. These genes were then used to screen CJD infected brain. A subset of these genes were detected as early as 20-30 days after inoculation, well before misfolded PrP and neurodegenerative changes appear. These upregulated genes, including L-selectin, myeloid cell recruitment factors, and pro-inflammatory activators, are all involved in inflammation and represent innate immune responses to the foreign CJD agent. Dr. Manuelidis and colleagues also developed a co-culture system using a mouse hypothalmic cell line to explore the infection process in the absence of immune cells. In this system, infection with one strain of CJD or scrapie can protect a cell from superinfection with a second TSE strain. Interestingly, this interference phenomenon is not related to the presence or absence of misfolded PrP.

 

[lansbergen]

http://tools.medicine.yale.edu/manuelidis/www/manuelidis_files/tse/25_nm_virion.pdf

Laura Manuelidis*

Yale Medical School, New Haven, Connecticut 06510

Abstract The transmissible spongiform encephalopathies (TSEs) such as endemic sheep scrapie, sporadic human Creutzfeldt-Jakob disease (CJD), and epidemic bovine spongiform encephalopathy (BSE) may all be caused by a unique class of ‘‘slow’’ viruses. This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein)
hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch’s postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and ‘‘amplified’’ prions have failed to produce significant infectivity. Moreover, the ‘‘wealth of data’’ claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain-specific forms of ‘‘infectious PrP’’ are proposed to explain the incompatible data. The ability of many ‘‘slow’’ viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host-immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1–5 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25–35 nm in diameter. This particle size can accommodate a viral genome of 1–4 kb, sufficient to encode a protective nucleocapsid and/or an enzyme required for its replication. Host PrP
acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain-specific molecules so important for diagnosis, prevention, and fundamental understanding.