Unclassified virus-like agents, transmissible spongiform encephalopathies and prion diseases

Unclassified virus-like agents, transmissible spongiform encephalopathies and prion diseases



There are a number of unclassified virus-like agents that are associated with, or considered to cause, disease in humans and animals (Table 128.1). The following chapters deal with two so-caused animal diseases of major importance, namely scrapie of sheep and goats, and bovine spongiform encephalopathy (BSE) of domestic cattle, though neither is currently reported in southern Africa. These two diseases belong to a group of diseases known as the subacute, transmissible spongiform encephalopathies (TSEs) caused by unconventional agents. The main characteristics of the TSEs are that they are progressive neurological disorders, generally affect adults, have long incubation periods often measured in years or decades, are always fatal and show spongiform changes in the brain. There is no effective prophylaxis or treatment for any TSE.

The unconventionality of the TSE agents is related to the fact that hosts mount no conventional immune response to infection and that the agents are extraordinarily resistant to physical and chemical inactivation using methods that are usually lethal to conventional bacteria, viruses and fungi. There is no currently available practical test to detect infected individuals.

Prions and prion protein

Prusiner8 in 1982 reported that novel proteinaceous infectious particles, which he named prions, cause scrapie. It was shown that a host sialoglycoprotein, known as PrP, is closely associated with infectivity and is probably the only structure necessary to produce disease. PrP is a cell membrane protein expressed in a number of body tissues of probably all mammals and some more lowly forms of animal life. The function of PrP is not yet understood. PrP is expressed most strongly in neurons. In disease the normal form of PrP (PrPSEN) is post-translationally converted to an insoluble, partially proteinase K-resistant form called PrPRES that may be the sole constituent of the infectious agent. Thus, since all the subacute TSEs are pathologically similar, they are also known as prion diseases. The nature of the TSE agent is, however, still not finally resolved. It may be an infectious protein (prion hypothesis), it may in addition have a genome, possibly a small nucleic acid in close association with PrP (virino hypothesis), or some still consider it an unconventional virus, claiming this hypothesis has not been disproved. New hypotheses and mechanisms are still being put forward but the prion hypothesis probably still dominates the scene.

Prions are not associated with detectable nucleic acid, thus resisting inactivation by procedures that modify nucleic acids. Both PrPSEN and PrPRES forms have an identical amino acid sequence. PrPRES is extremely heat resistant and is not inactivated at 100°C for 30 minutes. It retains its infectivity for many months in 10 to 12 per cent formaldehyde, tolerates a wide range of pH between 2,5 to 10,5 and is resistant to several enzymes. It is also resistant to ultraviolet light and ionising radiation, but is sensitive to 90 per cent phenol and to sodium dodecylsulphate.

Scrapie (rida)
Transmissible mink encephalopathy
Chronic wasting disease
Bovine spongiform encephalopathy
Feline spongiform encephalopathy
Creutzfeldt-Jacob disease
Gerstmann-Sträussler-Scheinker syndrome
Sheep and goats
Mule deer and elk
Domestic cats

Table 128.1  Prion-associated diseases

Prion protein is encoded by a cellular gene that appears to be most active in nerve cells. The gene that encodes PrP is present in normal and in spongiform encephalopathy-affected brain. PrPSEN is a sialoglycoprotein found in cell membranes of normal mammals. Mutations in the gene encoding for the naturally produced PrPSEN can modulate the development of a prion disease or even lead to an encephalopathy in the absence of any infectious process. PrPRES is also a glycoprotein and accumulates within the body of the cell. It is thought to have a half-life many times that of PrPSEN. The protein in diseased brains undergoes a posttranslational, probably conformational, alteration that causes it to be resistant to proteinase K digestion. For the infection to proceed, the newly synthesized prions must leave the cell of origin and transfer to other cells in the same animal to create an increasing number of modified cells and pathological change.

Number and geographical distribution of human and animal TSEs

Until 1985 six TSEs were known, three in humans and three in animals. The human diseases are all rare. They include kuru, affecting only the Fore-speaking people of Papua New Guinea, Creutzfeldt-Jakob disease (CJD) that occurs worldwide at an average annual prevalence of one to two per million, and Gerstmann-Sträussler-Scheinker (GSS) disease/ syndrome. Approximately 50 families with GSS mutations have been identified. Creutzfeldt-Jakob disease exists in four forms: sporadic (c. 85 per cent, cause unknown), familial (10 to 15 per cent, caused by mutations in the PrP gene), iatrogenic CJD (rare and due to historical medical accidents) and new variant (see below). A review by Ironside of prion diseases in humans has been published.6

The three animal diseases are scrapie of sheep and goats that has...

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