Table of Contents
Overview
Subviral pathogens are infectious agents that are even simpler than viruses. They lack at least one essential feature of a “typical” virus, such as a full set of genes or a protein coat, yet they can still replicate and cause disease. In humans, the most important subviral pathogens are:
- Viroids (primarily plant pathogens; discussed separately)
- Prions (protein-only infectious agents; important human pathogens)
- Defective (satellite) viruses and virus-like particles (which need “helper” viruses)
This chapter focuses on how these unusually simple agents can still act as pathogens, with an emphasis on prions in humans.
What Makes a Structure “Subviral”?
Typical viruses contain:
- Nucleic acid (DNA or RNA) with several genes
- A protein coat (capsid), often with an envelope
- All the information needed to hijack host cells and make new viruses
Subviral agents:
- Are smaller and simpler than viruses
- Lack some of these components (for example, no genes, or no capsid of their own)
- Depend heavily on host cell machinery and sometimes on other viruses to replicate
- Often have unusual replication or transmission mechanisms
Their simplicity challenges the usual boundary between living and nonliving structures and forces biology to rethink what counts as an “infectious agent.”
Prions: Protein-Only Infectious Agents
Prions are the best-known subviral human pathogens. They are infectious particles made only of protein, without any nucleic acid.
Molecular Nature of Prions
- The normal version of the prion protein in humans is called $PrP^C$ (“cellular prion protein”).
- It is produced by our own cells, especially in the brain, and is encoded by a normal human gene.
- In prion disease, the same protein appears in a misfolded, pathogenic form called $PrP^{Sc}$ (“scrapie” type, first described in sheep).
Key differences:
- $PrP^C$:
- Mostly $\alpha$-helical structure
- Soluble, not aggregated
- Sensitive to normal cellular degradation (proteases)
- $PrP^{Sc}$:
- Rich in $\beta$-sheet structure
- Tends to aggregate into fibrils and plaques
- Relatively resistant to proteases and to many standard disinfection methods
Mechanism of Prion Propagation
Prions replicate without nucleic acids by acting as templates for misfolding:
- $PrP^{Sc}$ comes into contact with normal $PrP^C$.
- The abnormal protein acts as a “mold,” causing $PrP^C$ to refold into the $PrP^{Sc}$ structure.
- Newly formed $PrP^{Sc}$ molecules aggregate and can convert more $PrP^C$.
- Aggregates accumulate, damage neurons, and lead to characteristic brain lesions (spongiform changes).
This “self-propagating misfolding” is the core of prion infectivity and is what makes prions unique among pathogens.
Prion Diseases (Transmissible Spongiform Encephalopathies)
Prion diseases are collectively called transmissible spongiform encephalopathies (TSEs) because:
- They are transmissible (can be passed between individuals under certain conditions).
- They cause sponge-like (spongiform) holes in brain tissue.
- They primarily affect the brain (encephalopathy).
Key human TSEs:
- Creutzfeldt-Jakob disease (CJD)
- Sporadic CJD: most common; cause is unclear, likely spontaneous misfolding of $PrP^C$.
- Familial CJD: due to inherited mutations in the prion protein gene that increase misfolding risk.
- Iatrogenic CJD: transmitted by medical procedures (e.g., contaminated surgical instruments, corneal transplants, or older preparations of human growth hormone).
- Variant CJD (vCJD)
- Linked to eating products from cattle with bovine spongiform encephalopathy (BSE, “mad cow disease”).
- Typically affects younger individuals and has somewhat different clinical and pathological features from sporadic CJD.
- Kuru
- Historically affected a population in Papua New Guinea.
- Transmission was associated with ritual cannibalism, especially ingestion of brain tissue.
- Incidence fell drastically when these practices stopped.
- Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI)
- Very rare, inherited prion diseases.
- Caused by specific mutations in the prion protein gene; show characteristic patterns of neurodegeneration.
Features of Prion Diseases
Shared characteristics:
- Very long incubation times (years to decades) between infection and symptoms.
- Progressive, irreversible damage to the central nervous system.
- Symptoms: rapidly progressive dementia, movement and coordination disturbances, behavioral changes, sometimes sleep disturbances.
- No effective cure; invariably fatal once clinical disease develops.
Transmission and Resistance
Prions can be transmitted by:
- Ingestion of contaminated tissue (especially brain and nervous tissue).
- Contaminated surgical instruments or transplants.
- Blood and blood products under certain circumstances (risk is low but considered in safety measures).
Notable properties:
- Extraordinary resistance to conventional methods of disinfection and sterilization:
- Heat and standard autoclaving conditions may not be fully effective.
- They survive many chemical disinfectants that readily inactivate viruses and bacteria.
- Special decontamination protocols are required (e.g., extended high-temperature autoclaving combined with strong chemicals, such as concentrated sodium hydroxide).
These properties make prions a specific challenge for hospital hygiene and for handling of medical instruments and biological materials.
Other Subviral Pathogens and Virus-Dependent Agents
Besides prions, other entities sometimes grouped as subviral or “subviral-like” involve defective viruses and satellite agents.
Defective and Satellite Viruses
Defective viruses:
- Have lost or lack part of the genetic information needed for independent replication.
- Require a helper virus to supply missing functions.
- Alone, they are noninfectious; together with a helper virus, they can replicate and sometimes contribute to disease severity.
Satellite viruses:
- Possess their own nucleic acid but depend on a helper virus for some replication steps or structural components.
- May modulate the outcome of infection by the helper virus, sometimes making the disease more severe, other times attenuating it.
In humans, an important medically relevant example is:
- Hepatitis D virus (HDV)
- A satellite virus that requires hepatitis B virus (HBV) for its envelope proteins.
- HDV alone cannot form infectious particles; co-infection or superinfection with HBV is necessary.
- HDV infection can lead to more severe liver disease than HBV alone and can accelerate progression to cirrhosis.
Although HDV is often categorized as a small RNA virus, its strict dependence on HBV for packaging and transmission places it conceptually close to other subviral agents.
Biological and Medical Significance of Subviral Pathogens
Subviral agents are important for several reasons:
- Public health relevance
- Prions and HDV cause severe, often fatal or chronic diseases.
- Their unusual stability (prions) or dependency relationships (HDV with HBV) affect control strategies.
- Conceptual significance in biology
- Prions show that information can be stored and propagated in protein conformation, not only in nucleic acids.
- Satellite and defective viruses illustrate complex interactions between pathogens and highlight that “virus” is not always a self-sufficient unit.
- Practical consequences
- Need for specialized decontamination procedures for prions.
- Screening and vaccination strategies for helper viruses (e.g., hepatitis B vaccination indirectly prevents HDV infection).
- Caution in medical procedures using human-derived materials and instruments exposed to nervous tissue.
Understanding subviral structures as pathogens broadens the concept of infection and shows that even extremely simple molecular assemblies can have profound effects on human health.