Soil as an Environmental Reservoir of Prion Diseases
Prions are recognized as misfolded, pathologic isoforms of the normal mammalian prion protein, which can uniquely cause infectious inherited or spontaneous disease. They are agents of transmissible spongiform encephalopathies (TSEs). The normal, benign, host-encoded forms of PrP are denoted PrPC, and the infectious disease-associated, misfolded conformers are designated PrPTSE. Earlier it was hypothesized that TSEs were caused by a new type of “slow virus” that was too small to purify but had virus-like phenotypes such as transmissibility and heritability. This was the predominantly held theory until 1982, when Stanley Prusiner proposed that the causative agent was exclusively a protein. He solidified the “protein-only” hypothesis which had been developing and termed the agent proteinacious infectious only, or prion. Prion diseases are a family of inevitably fatal neurodegenerative disorders affecting a variety of mammalian species, including human diseases such as Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), Kuru, Fatal Familial Insomnia (FFI) and Gerstmann-Sträussler-Scheinker Syndrom (GSSS). Animal prion diseases include chronic wasting disease (CWD) in North American deer, elk and moose; scrapie in sheep and goats, bovine spongiform encephalopathy (BSE: “mad cow” disease) in cattle, and transmissible mink encephalopathy (TME) in mink. These diseases are characterized by long incubation periods, spongiform degeneration of the brain and accumulation of an abnormally folded isoform of the prion protein, designated PrPSc, in brain tissue. The unusual nature of prions has created a formidable challenge for detection and study of the agent. Studies have shown prions to adsorb strongly to soil components, remain infectious and persist for years. Indirect transmission most likely occurs through incidental and geophagic ingestion of soil or other contaminated fomites, as well as deer sign-post behavior such as scraping and marking overhanging branches.
Scrapie has been known in sheep since the early eighteenth century. Clinically infected sheep exhibit the obvious feature of excessive rubbing and scratching of the skin. The terminus “scrapie” goes back to this symptom. The origin of the scrapie agent is unknown, but a familial pattern exists in natural sheep scrapie suggesting that genetics and, possibly, vertical transmission are important. Scrapie has a world-wide distribution and has been documented wherever sheep are raised, with the exception of Australia and New Zealand. In the 1920s a similar neurodegenerative disease in humans was recognized which was later named Creutzfeldt-Jakob Disease (CJD) after the discovering physicians, Hans Creutzfeldt and Alfons Jakob. In the 1960s, Kuru, a devastating disease of the Fore people in Papua New Guinea, was also identified as a TSE, with an epidemiology suggesting transmission through cannibalistic traditions. CWD was identified in the late 1960s and recognized as a TSE in 1980.
Clinical manifestations of prion diseases generally include progressive neurologic deterioration resulting in ataxia, dementia, and behavioral changes. The diagnostic hallmark of a TSE disease is the presence of extracellular plaques composed of prion aggregates in neurologic or lymphatic tissues. Prion plaque deposits are generally associated with spongiform destruction to brain tissue and elevated levels of astrogliosis in the central nervous system (CNS). Although there are examples of prion transmission through iatrogenic means or infection through blood or tissue grafts, the primary and most natural route is through oral-nasal exposure. This is true for Kuru, BSE, vCJD, transmissible mink encephalopathy (TME), scrapie and CWD. Upon ingestion, studies suggest that the prion infects the gut associated lymphatic tissue, which includes M cells, Peyer’s patches (PP) and the follicle-associated epithelium. In challenge studies the PPs appeared to be the first infected tissue, with detectable prions associated with lymphatic tissue in as early as 1 week of oral inoculation. M cells sample the prions from the intestinal lumen then traffic the prion to the PP. Once inside the PP the prion is trafficked by macrophages and DCs to germinal centers in lymph tissues including mesenteric lymph node, retropharyngeal lymph node and spleens, where they are transferred to cells of the immune system (follicular dendritic cells: FDCs). Studies suggest that the process of prion replication and retrograde neuroinvasion is dependent on FDCs and their proximity to the enteric nervous system.
The general nomenclature for the infectious agent is PrPSc, for the pathologic isoform associated with scrapie, or generically PrPRES since the isoform is generally resistant to protease degradation. Other biochemical hallmarks include conversion of the normal α helical rich PrPC conformation to a β sheet rich PrPRES form. This conformational change allows for the formation of insoluble amyloidogenic aggregates. However, the exact tertiary structure of the prion protein in either conformation up to now is not completely clear.
Prions and their resulting TSE diseases, were hardly known to the general public until the occurrence of BSE and the epidemiologically linking it to vCJD. The possibility of prion transmission to humans triggered a large research effort into BSE, CJD, vCJD, scrapie, CWD and other prion diseases. This extensive research on prions has led to the recognized commonalities between prion diseases and other protein misfolding diseases. The “prion like” or prionoid term is now applied to diseases that include Alzheimer’s disease, Parkinson’s disease, ALS, Huntington’s disease and more. While most recognized protein misfolding diseases are not considered transmissible at the host level, the cell to cell and tissue to tissue transmission that occurs in the host is very similar to prion misfolding, replication and transmission. These diseases, similar to prion diseases, can result from inherited or acquired mutations, spontaneous misfolding events, or environmental or stress factors not yet identified.
Transmission of prion diseases orally is well-known which raises concern about interspecies transmission of animal TSEs to humans. For example, interspecies transmission of BSE to sheep, felines and ungulates has occurred which is regarded to be responsible for the emergence of vCJD in humans. The primary infection pathway for BSE that emerged in the UK in the mid-1980s has probably been via dietary exposure to industrial animal feed. However, risks of transmission of PrPBSE from cattle to humans are reduced by preventing tissues, including brain, spinal cord, dorsal root ganglia, trigeminal ganglia, eyes and tonsils for ruminants 30 months or older and the distal ileum of all ruminants, designated as specified risk material, from entering the food chain. Removal and management of SRM brings up the obvious problem of safe disposal. The disposal of specified risk material wastes infected with PrPTSE is challenging, as the infectivity of these materials exhibits resistance to inactivation by a wide range of physicochemical methods, which are commonly used for disinfection. Currently approved decontamination procedures for specified risk material include thermal or alkaline hydrolysis, incineration, gasification and combustion with extreme temperature and pH requirements. Although these procedures are highly successful in destroying all infectious materials, they are difficult to implement, particularly when a large volume of specified risk material requires decontamination. As a consequence, specified risk materials are still being rendered and deposited in landfills in several countries. However, this procedure does not eliminate risk, because PrPTSE may still be present in these materials, and the potential for leakage from landfills may result in contamination of the environment.
KeywordsPrion diseases Creutzfeld-Jakob disease Gerstmann-Sträussler-Scheinker syndrome Fatal familial insomnia Kuru Prions in the environment Prion transmission Pathogenesis Therapy Public health management Treatment of environmental material infected with prions Treatment of wastewater
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