■ Viroids are phytopathologically significant, noncoding RNA molecules that interfere with cellular regulation as antisense RNA. The hepatitis D virus has some structural similarity to viroids.
Prions consist of a cell-coded protein (PrP: prion protein) altered in its conformation and by point mutations. They are infectious and can cause normal cellular PrP to assume the pathological configuration. They cause the spongiform encephalopathies (Creutzfeldt-Jakob disease, CJD) in the classic and new variants (nvCJD), the Gerstmann-Straussler-Scheinker (GSS) syndrome, and animal diseases (scrapie, BSE) characterized by neuronal vacuolization and loss and so-called amyloid plaques.
Prevention: exposure prophylaxis (iatrogenic and alimentary transmission). ■
Viroids were discovered at the end of the sixties during investigations of plant diseases. They consist of infectious, naked ssRNA in closed circular form with extensive base-pairing to form a rod-shaped strand 50 nm long. This RNA is 10 times smaller than the smallest viral nucleic acid and comprises, depending on the type, only 250-350 nucleotides. It does not function as mRNA and 8 does not code for proteins. Its mode of replication is unknown, but certainly involves cellular enzymes.
Viroids cause a number of plant diseases with considerable economic impact. The following hypothesis is currently under discussion to explain their pathogenicity mechanism: viroids possess complementary sequences to cellular 7S RNA, comprising, together with six proteins, the "signal recognition particle." This particle controls the posttranslational membrane insertion of proteins. Viroids can thus interfere as "antisense (or interfering) RNA" with the function of 7S RNA and thus with membrane formation.
The only significant human pathogen structurally related to the viroids is the hepatitis D pathogen (HDV, delta agent, see p. 429). HDV consists of a viroidlike, also circular, RNA into which an antisense RNA coding for the delta agent is inserted.
Pathogen. Attention was first drawn to certain encephalopathic agents whose physical properties differed greatly from those of viruses. For instance, they showed very high levels of resistance to sterilization and irradiation procedures. It was later determined that these pathogens—in complete contrast to viruses and viroids—require only protein, and no nucleic acid, as the basis of their infectivity and pathogenicity. This gave rise to the term "prion" for "proteinaceous infectious particle." An intensive search for nucleic acid in the "particles" was fruitless.
Prions are misfolded forms of a cellular protein. They consist of only a single protein (PrP, prion protein), which naturally occurs, for example, on the surface of neurons. The region coding for this protein of approx. 35 kDa is located in a single exon and is derived from a cellular gene expressed in both healthy and diseased brains. Disease-associated PrP (the best-known prion is the scrapie pathogen, the protein of which is called PrPsc [sc for scrapie]), is a mutant, slightly shortened (27-30 kDa) form of the normal PrPc (c for cell). It differs from normal PrPc in its altered configuration, its nearly complete resistance to proteases and in the fact that it tends to accumulate inside the cell.
Pathogenesis. Infectious PrPsc can transform naturally occurring PrPc into PrPsc, resulting in an autocatalytic chain reaction in which mainly the pathological protein is produced. This is why mice lacking the gene for PrP (genetically engineered "knockout mice") cannot be infected with the pathological PrPsc prion. Deposits of large amounts of the pathological protein in the form of so-called amyloid plaques are visible under a microscope in brain tissue from infected humans and animals.
Clinical picture. The following encephalopathies are considered to be caused by prion infections:
■ Creutzfeldt-Jakob disease (CJD)
■ Gerstmann-Straussler-Scheinker (GSS) syndrome
■ Transmissible mink encephalopathy (TME)
■ Bovine spongiform encephalopathy (BSE, "mad cow disease")
474 8 Viruses as Human Pathogen ^^^^^^^^^^^^^^^^^^^^^^^
All of these diseases are designated as transmissible encephalopathies characterized by incubation periods of a number of years, long durations of disease (one to several years in humans) and lethal courses with motor disturbances (animals) and progressive dementia (humans). Histologically, the brain shows no inflammation, but rather vacuolization of neurons, loss of neurons, proliferation of glial cells, and amyloid plaques (see above).
Diagnosis. The diagnostic procedure is histological. Since there is no immune response to the pathological PrP, serodiagnostic methods are useless. The pathological protein can, however, be detected in lymphoid tissue biopsies using monoclonal antibodies.
Epidemiology. CJD, which occurs sporadically (one case per million inhabitants per year) is produced anew in every case by mutations in PrPc. The disease can be transmitted iatrogenically (brain electrodes, corneal transplants). The pathogenicity of the GSS prion (PrPgss) is based on a single amino acid change. Genetic factors also appear to have a predisposing effect in view of the existence of familial forms of GSS. Kuru is a disease that was spread in New Guinea by cannibalistic rites, probably originating with a case of CJD. Kuru no longer occurs today.
Alimentary transmission is possible in animals. PrPsc was transmitted to cattle by feeding them animal meal made from scrapie-infected sheep remains, resulting in BSE. Despite the fact that transmission of prions from one species to another is not a simple process in principle, BSE prions were transmitted to humans by the alimentary route, resulting in nvCJD. This route of transmission was confirmed by structural analyze of the BSE and nvCJD prions.
8 From 1995, when the first nvCJD patient died, to the end of 2000,51 cases of CJD with lethal outcome have been described. In contrast to classic CJD, these infections occurred in young people, whereby the incidence of nvCJD in older persons can be masked by dementias from other causes. The expected outbreak of nvCJD because of the BSE epidemic is currently a topic of extensive discussion.
As a result of this new disease threat, some countries have now prohibited the feeding of animal meal to certain kinds of livestock (in particular ruminants).
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