21.4 Other Acellular Entities: Prions and Viroids

Prions and Viroids

Prions and viroids are infectious agents that don't fit neatly into the usual categories of pathogens. Prions are misfolded proteins that cause fatal brain disorders in animals, and viroids are tiny circular RNA molecules that infect plants. Neither one is a cell or a virus, yet both can spread and cause serious disease.

What makes them so unusual is their simplicity. Prions contain no nucleic acid at all, and viroids have no protein coat. Studying them pushes the boundaries of what we consider "infectious" and shows that even minimal biological structures can be devastating.

Prions in Neurodegenerative Diseases

Prions are infectious agents made entirely of protein, with no DNA or RNA. The infectious form is a misfolded version of a normal cellular protein.

• Every healthy mammalian brain produces a protein called PrP$^C$ (the normal cellular prion protein).
• The infectious form, PrP$^{Sc}$ (prion protein scrapie), has the same amino acid sequence but a different three-dimensional shape.
• When PrP$^{Sc}$ contacts normal PrP$^C$, it forces PrP$^C$ to refold into the abnormal shape. This creates a chain reaction: each newly misfolded protein can convert more normal proteins.

The misfolded proteins clump together into amyloid plaques that accumulate in the brain. These plaques destroy neurons and leave the brain riddled with tiny holes, giving it a sponge-like appearance under a microscope. That's why prion diseases are collectively called transmissible spongiform encephalopathies (TSEs).

Examples of prion diseases:

• Kuru was identified in the Fore people of Papua New Guinea, where it spread through ritualistic cannibalism involving consumption of brain tissue from deceased relatives.
• Bovine spongiform encephalopathy (BSE), or "mad cow disease," spread among cattle through feed that contained prion-infected meat and bone meal.
• Creutzfeldt-Jakob disease (CJD) occurs in humans. It can arise spontaneously, be inherited through mutations in the prion protein gene, or be acquired (for example, variant CJD has been linked to consumption of BSE-contaminated beef).

All prion diseases are currently untreatable and fatal. Because the infectious agent is a protein rather than a nucleic acid, prions resist standard sterilization methods like UV radiation and chemical disinfectants that would destroy DNA or RNA.

Structure and Replication of Viroids

Viroids are the smallest known infectious agents. They consist of a short, single-stranded, circular RNA molecule with no protein coat and no genes that encode proteins.

• Viroid RNA ranges from about 246 to 401 nucleotides, far smaller than even the smallest viral genomes.
• The RNA has extensive self-complementary regions, meaning parts of the strand base-pair with other parts of itself, forming a highly structured rod-like shape with double-stranded segments.

Since viroids encode no proteins of their own, they depend entirely on host cell machinery to replicate. Replication takes place in the nucleus (for most viroids) or in chloroplasts:

1. Host RNA polymerase II uses the circular viroid RNA as a template, producing long linear copies that contain multiple repeats of the viroid sequence (multimeric RNA).
2. Host enzymes (or, in some viroids, the RNA itself through ribozyme activity) cleave the multimeric strand into individual viroid-length units.
3. Each unit circularizes through self-ligation or with the help of host enzymes.
4. The new circular RNA molecules serve as templates for further rounds of replication.

Viroids cause disease by interfering with host gene expression. They can interact with host proteins and trigger RNA silencing pathways, which leads to degradation of the plant's own mRNAs. Symptoms include stunted growth, leaf distortion, and reduced crop yield. One well-known example is Potato spindle tuber viroid (PSTVd), which causes significant agricultural damage.

Transmission of Prions vs. Viroids

These two agents spread in very different ways, reflecting the different organisms they infect.

Prion transmission:

• Most commonly acquired through ingestion of infected tissue (contaminated feed in cattle, or historically, cannibalism in humans)
• Can also be inherited when a person carries a mutation in the gene encoding PrP$^C$ that makes the protein more likely to misfold spontaneously
• Sporadic cases arise without any known exposure or inherited mutation
• Prions are not transmitted through casual contact or airborne routes

Viroid transmission:

• Primarily spread by mechanical means, such as contaminated pruning tools, equipment, or hands during plant handling
• Grafting infected plant material onto healthy plants is another common route
• Some viroids can also spread through pollen or seeds, though this varies by species

One shared feature: neither prions nor viroids require a biological vector (like an insect) for transmission. Prions pass directly between animals through ingestion, and viroids pass directly between plants through physical contact or propagation practices.