6.4 Viroids, Virusoids, and Prions

Viroids, virusoids, and prions are infectious agents that don't fit neatly into the usual categories of pathogens. They lack cells, and some lack nucleic acids entirely, yet they still cause serious diseases in plants and animals.

What makes them worth studying is how they force you to rethink what it takes to be "infectious." Viroids are just naked RNA. Prions are just misfolded proteins. Neither one looks like it should be able to replicate or spread, but both do.

Viroids, Virusoids, and Prions

Structure and replication of viroids

Viroids are the smallest known infectious agents. Each one is nothing more than a short, single-stranded, circular RNA molecule with no protein coat and no genes that encode proteins. Their genomes range from about 246 to 467 nucleotides, which is tiny even compared to the smallest viruses. Examples include potato spindle tuber viroid (PSTVd) and chrysanthemum stunt viroid.

Because viroids don't encode their own proteins, they're completely dependent on the host cell's machinery. Replication takes place in the nucleus of host plant cells and follows these steps:

1. The viroid's (+) strand RNA enters the host cell nucleus.
2. The host's RNA-dependent RNA polymerase (RdRP) uses the (+) strand as a template to synthesize a complementary (-) strand RNA.
3. That (-) strand then serves as a template for producing new (+) strand RNA copies.
4. The newly synthesized (+) strand molecules are cleaved into individual units and circularized to form mature viroids.

Some viroids have ribozyme activity, meaning the RNA itself can catalyze its own cleavage during step 4. This is a key distinction from viruses: viroids have no capsid, a far smaller genome, and encode zero proteins.

Virusoids vs satellite viruses

Both virusoids and satellite viruses depend on a helper virus to replicate, but they differ in important ways.

• Virusoids are small, circular, single-stranded RNA molecules (220–388 nucleotides). They don't encode their own coat protein. Instead, they get packaged inside the coat protein of their helper virus. Examples include the hepatitis delta virusoid and velvet tobacco mottle virusoid.
• Satellite viruses have larger genomes (800–1,400 nucleotides) and do encode their own coat protein. Examples include satellite tobacco necrosis virus and satellite panicum mosaic virus.

The shared feature is that both rely on the helper virus's replication machinery, particularly enzymes like RdRP. They essentially compete with the helper virus for those replication resources, which can sometimes modulate the severity of the helper virus's infection.

Prions and neurodegenerative diseases

Prions are unlike every other infectious agent covered in this unit because they contain no nucleic acid at all. A prion is simply a misfolded version of a normal cellular protein.

• The normal form of the prion protein is called $PrP^C$ (C for "cellular").
• The misfolded, infectious form is called $PrP^{Sc}$ (Sc for "scrapie," the sheep disease where prions were first studied).

Prion replication works through a conformational chain reaction: $PrP^{Sc}$ physically contacts normal $PrP^C$ molecules and induces them to refold into the $PrP^{Sc}$ shape. Those newly misfolded copies then convert more $PrP^C$, and the process snowballs.

The diseases prions cause are called transmissible spongiform encephalopathies (TSEs) because the brain tissue develops a sponge-like appearance as neurons die.

• Human TSEs: Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Kuru
• Animal TSEs: bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle, scrapie in sheep

Neurodegeneration progresses through several mechanisms:

1. Misfolded $PrP^{Sc}$ proteins aggregate into insoluble amyloid plaques in brain tissue.
2. These aggregates are toxic to neurons, causing neuronal loss and synaptic dysfunction.
3. Glial cells become activated in response, triggering neuroinflammation that further accelerates damage.

One reason prion diseases are so difficult to treat is that $PrP^{Sc}$ is remarkably resistant to standard sterilization methods, including heat, UV radiation, and chemical disinfectants that would destroy nucleic acid-based pathogens.

RNA processing in viroids and virusoids

RNA processing is central to how viroids and virusoids complete their life cycles. During replication, long concatemers (repeated copies linked end-to-end) must be cleaved into individual units and then ligated into circular form.

Hammerhead ribozymes are the key players here. These are small catalytic RNA motifs found in certain viroids and virusoids that catalyze site-specific self-cleavage of the RNA strand. This is significant because it demonstrates that RNA can act as both genetic material and an enzyme, a concept that supports the RNA world hypothesis you may encounter in other parts of your coursework.