Some hereditary agents are extremely small

KEY TERMS:

• A viroid is a small infectious nucleic acid that does not have a protein coat.
• Virion is the physical virus particle (irrespective of its ability to infect cells and reproduce).
• A subviral pathogen is an infectious agent that is smaller than a virus, such as a virusoid.
• Scrapie is a infective agent made of protein.
• A prion is a proteinaceous infectious agent, which behaves as an inheritable trait, although it contains no nucleic acid. Examples are PrP^Sc, the agent of scrapie in sheep and bovine spongiform encephalopathy, and Psi, which confers an inherited state in yeast.
• PrP is the protein that is the active component of the prion that causes scrapie and related diseases. The form involved in the disease is called PrP^Sc.

KEY CONCEPTS:

• Some very small hereditary agents do not code for protein but consist of RNA or of protein that has hereditary properties. 

Viroids are infectious agents that cause diseases in higher plants (for review see Diener, 1999). They are very small circular molecules of RNA. Unlike viruses, where the infectious agent consists of a virion, a genome encapsulated in a protein coat, the viroid RNA is itself the infectious agent. The viroid consists solely of the RNA, which is extensively but imperfectly base paired, forming a characteristic rod like the example shown in Figure 1.46. Mutations that interfere with the structure of the rod reduce infectivity.

A viroid RNA consists of a single molecular species that is replicated autonomously in infected cells. Its sequence is faithfully perpetuated in its descendants. Viroids fall into several groups. A given viroid is identified with a group by its similarity of sequence with other members of the group. For example, four viroids related to PSTV (potato spindle tuber viroid) have 70-83% similarity of sequence with it. Different isolates of a particular viroid strain vary from one another, and the change may affect the phenotype of infected cells. For example, the mild and severe strains of PSTV differ by three nucleotide substitutions.

Viroids resemble viruses in having heritable nucleic acid genomes. They fulfill the criteria for genetic information. Yet viroids differ from viruses in both structure and function. They are sometimes called subviral pathogens. Viroid RNA does not appear to be translated into protein. So it cannot itself code for the functions needed for its survival. This situation poses two questions. How does viroid RNA replicate? And how does it affect the phenotype of the infected plant cell?

Replication must be carried out by enzymes of the host cell, subverted from their normal function. The heritability of the viroid sequence indicates that viroid RNA provides the template.

Viroids are presumably pathogenic because they interfere with normal cellular processes. They might do this in a relatively random way, for example, by sequestering an essential enzyme for their own replication or by interfering with the production of necessary cellular RNAs. Alternatively, they might behave as abnormal regulatory molecules, with particular effects upon the expression of individual genes (for review see Diener, 1986).

An even more unusual agent is scrapie, the cause of a degenerative neurological disease of sheep and goats. The disease is related to the human diseases of kuru and Creutzfeldt-Jakob syndrome, which affect brain function.

The infectious agent of scrapie does not contain nucleic acid. This extraordinary agent is called a prion (proteinaceous infectious agent) (for review see Prusiner, 1998). It is a 28 kD hydrophobic glycoprotein, PrP. PrP is coded by a cellular gene (conserved among the mammals) that is expressed in normal brain. The protein exists in two forms. The product found in normal brain is called PrP^c. It is entirely degraded by proteases. The protein found in infected brains is called PrP^sc. It is extremely resistant to degradation by proteases. PrP^c is converted to PrP^sc by a modification or conformational change that confers protease-resistance, and which has yet to be fully defined (McKinley, Bolton, and Prusiner, 1983).

As the infectious agent of scrapie, PrP^sc must in some way modify the synthesis of its normal cellular counterpart so that it becomes infectious instead of harmless (see 23.24 Prions cause diseases in mammals). Mice that lack a PrP gene cannot be infected to develop scrapie, which demonstrates that PrP is essential for development of the disease (Bueler et al., 1993).