These infectious agents are simpler than viruses. Viroids cause, predominantly, plant diseases such as potato spindle-tuber disease. They consist of circular, single-stranded RNA, usually 250 to 370 nucleotides long. In plants they are found mainly in the nucleolus, but little else is known of the pathogenic mechanisms that they employ. Human disease due to viroids is not yet recognised.
Prions are putative infectious agents so-called because they are proteinaceous infectious particles (the originator changed it from prom). Although there is not universal agreement that they exist in vivo, the evidence for them is now considerable. The best studied is the prion that causes a degenerative disorder of the central nervous system of sheep, scrapie. This agent appears to be a 33-35 kDa hydrophobic protein which has been termed PrP (for prion protein). The gene that encodes for this protein exists in normal sheep, but the product in diseased animals has a mutant peptide sequence and an abnormal isoform with 3-pleated sheets replacing a-helical domains; the normal cellular protein is termed PrPc, the abnormal PrPsc. The abnormal protein further differs from the normal cellular protein by being insoluble in detergents, highly resistant to proteases and having a tendency to aggregate. Prion proteins have been shown to be infectious and to have a high but not absolute degree of species specificity.
An alternative hypothesis for the infectious agent of scrapie has been the virino. This putative agent has a tiny, as yet undetectable, scrapie-specific nucleic acid coated in PrP There is currently no evidence for the existence of this agent, but it offers a plausible explanation for the strain variation that is known to occur in scrapie.
Transmissible degenerative encephalopathies
Scrapie is a transmissible degenerative encephalopathy (TDE) of sheep, and many other ungulates suffer this disorder. It is now recognised that TDEs also occur in man .
The features of a TDE are:
• the presence of aggregates of prion proteins into amyloid fibrils
• the presence of ‘holes’ in the neuronal matrix (‘spongiform’ degeneration) caused by amyloid
• a long incubation period (several months to many years)
• that they are rapidly progressive
• clinical presentation with cognitive impairment, ataxia, myoclonus and extrapyramidal signs.
The tentative diagnosis of human TDE is made from the clinical features, which occur usually in patients between 40 and 70 years of age; ‘variant’ Creutzfeld-Jakob (vCJD) disease, however, involves younger patients. Confirmation of the diagnosis currently depends on the neuropathological features found at post-mortem, although newer methods based on detection of the abnormal PrP by labelled-specific antibody are becoming more widely available and constitute the definitive test. Currently there is no treatment, so prevention forms the bedrock of control. Brain and spinal cord appear to be the predominant reservoir of infection, and transmission has been shown to occur with infected corneal and dura mater grafts, growth hormone and gonadotrophin injections and the use of contaminated neurosurgical instruments. Kuru is thought to have arisen because of cannibalism of human brains. There is also a genetic component to disease susceptibility, with 10% of CJD cases being familial and a higher prevalence of sporadic CJD in, for example, Israeli Jews of Libyan origin. The human prion protein gene is located on chromosome 20, and homozygosity at codon 129 (methionine or valine) confers susceptibility to CJD, although this mutation is not directly linked to disease causation. Such markers may be useful in the future for diagnostic and screening purposes.