Lecture 15: Subviral Agents

Lecture 15: Subviral Agents

Overview of Viruses

  • Definition of Viruses: A virus is composed of:

    • Nucleic Acid Genome: Can be either DNA or RNA.

    • Protein Capsid: Protective protein shell surrounding the genome.

    • Lipid Envelope: May or may not be present.

  • Focus on Non-Living Infectious Particles: Besides viruses, there are other infectious agents that do not conform to the traditional definition of a virus.

Subviral Agents

  • Definition: Subviral agents are transmissible agents that do not fit the conventional definition of a virus.

  • Examples of Subviral Agents:

    • Viroids

    • Satellite viruses

    • Prions

Viroids

  • Definition: Viroids are small, circular single-stranded RNA molecules.

  • Characteristics:

    • Length: 246-401 nucleotides.

    • Infectious pathogens lacking a protein coat or lipid envelope.

    • Also referred to as “sub-viral agents.”

  • Families of Viroids:

    1. Pospiviroidae:

    • Features: Rod-like secondary structure.

    • Replication: Occurs in the nucleus.

    1. Avsunviroidae:

    • Features: Branched secondary structures.

    • Replication: Occurs in the chloroplast.

Viroid Replication

  • Replication Mechanism:

    • Utilizes host RNA polymerase II, typically used for synthesizing messenger RNA from DNA, to facilitate rolling circle replication of new viroid RNA.

    • Viroids employ ribozymes with self-cleaving mechanisms (in Avsunviroidae) or host Rnase III (in Pospiviroidae) to cleave longer-than-unit RNA strands.

Transmission of Viroids

  • Viroids exclusively infect plants.

  • Transmission Methods:

    • Cross-contamination resulting from mechanical damage in horticulture or agriculture.

    • Plant-to-plant transmission via leaf contact.

    • Insect vectors such as aphids.

Example: Potato Spindle Tuber Disease

  • Pathogen: Potato Spindle Tuber Viroid (PSTVd).

  • Significance: First viroid discovered, identified in 1971 by Theodor Otto Diener.

  • Hosts: Primarily infects potatoes and tomatoes.

  • Symptoms in Potatoes:

    • Color changes in foliage.

    • Smaller leaf size.

    • Spindle-shaped elongation of tubers.

    • Slower sprouting rate.

  • Symptoms in Tomatoes:

    • Stunted growth.

    • Yellow or purple, curled leaves.

    • Leaf vein necrosis.

    • Difficulty in ripening leading to small, green tomatoes.

Emergence of Viroids

  • Hypothesis on Emergence:

    • RNA World Hypothesis: Proposes that RNA was the primordial molecule and transitioned to contemporary cell structures.

    • Stages of Transition:

    1. RNA formation from inorganic sources.

    2. RNA self-replication.

    3. Catalysis by RNA leading to protein synthesis.

    4. Membrane formation, altering internal chemistry for new functionality.

    5. Transition to DNA being the master template.

    6. Proteins becoming catalysts for cellular activities.

  • Current Perspectives on Life: DNA is recognized as the primary genetic material and complex proteins hold catalytic roles in modern biology.

Evidence Supporting RNA World Hypothesis

  • Viroids: They are self-replicating RNA, fitting the hypothesis of an RNA-based system.

  • Ribosomes: Composed largely of RNA, indicating an RNA role in early life forms.

  • Ribozymes: Catalytic RNA molecules demonstrate the enzymatic potential of RNA.

Challenges to RNA World Hypothesis

  • Instability of RNA: RNA's shorter stability raises concerns about long-term information preservation.

  • Complexity of Early RNA: The intricate structures necessary for catalytic activity might pose formation challenges in prebiotic conditions.

Alternative Theories of Viroid Emergence

  • De Novo Evolution: Suggests random RNA sequences folding into self-replicating structures.

  • Cellular Origin: Proposes that viroids originated from small RNA within cells, evolving autonomously through mutations.

  • Recombination Events: Viroids may have arisen from RNA recombination within host cells.

Viroid-Like Elements

Satellite RNAs

  • Description: Small non-coding RNA molecules that depend on a helper virus for replication.

  • Functions: Can cause disease by directing RNA silencing against critical host genes while occasionally mitigating the disease impact.

Satellite Viruses

  • Definition: These are subviral particles that require another virus (helper virus) for replication.

  • Identification: Known as defective viruses; they encode their own capsid proteins but rely on helper viruses for replication.

  • Examples:

    • Adeno-associated Virus (AAV): Requires co-infection with adenovirus or herpesvirus.

    • Hepatitis D virus (HDV): Requires co-infection with Hepatitis B Virus.

Ambiviruses

  • Definition: Hybrid infectious agents incorporating features from both viruses and viroids.

  • Components: Contain RdRp (like viruses) and ribozymes (like viroids), affecting fungi.

Virophages

  • Definition: Double-stranded DNA viruses from the Lavidaviridae family that depend on co-infection with a giant dsDNA virus of the Mimiviridae family.

  • Replication: Occurs intracellularly in the cytoplasmic factory of the co-infecting giant virus.

  • Features: Some genomes encode integrase proteins, allowing persistence as provirophages in host chromosomes.

Characteristics of Virophages

  • Parasitic Nature: Virophages can inhibit viral replication in coinfected cells, potentially increasing the survival rates of the host cells.

Prions

  • Definition: Prions are abnormally folded proteins that induce misfolding in normal proteins.

  • Key Terms:

    • Prion: Stands for “Proteinaceous Infectious Particle.”

    • Misfolded Proteins: Proteins that change structure, ultimately affecting other proteins’ conformations.

    • Transmission: Does not involve nucleic acids.

    • Mechanisms of Misfolding:

    • Sporadic mutations.

    • Exposure to existing misfolded proteins.

Prion Diseases

  • Description: Prion diseases are characterized by fatal and untreatable neurodegeneration in humans and animals, collectively referred to as Transmissible Spongiform Encephalopathy (TSE).

  • Spread: Via contaminated meat, bodily fluids, surgical equipment, and cannibalism.

  • Mechanism: Prions interact with the brain's normal prion proteins (PrP), causing a cascade of misfolding.

Specific Prion Diseases

Transmissible Spongiform Encephalopathy

  • Includes diseases like:

    • Scrapie in sheep.

    • Chronic Wasting Disease (CWD) in deer.

    • Bovine Spongiform Encephalopathy (BSE) also known as mad cow disease.

    • Creutzfeldt-Jakob Disease (CJD) in humans.

Bovine Spongiform Encephalopathy (BSE)

  • Symptoms: Abnormal behavior, posture issues, difficulty walking, and weight loss.

  • Progression of Disease: Symptoms typically manifest 3-6 years post-infection, with death occurring within weeks to months post-symptom onset.

  • Prevention: Enforced bans on certain animal feed types to prevent transmission.

Impact of BSE Outbreaks

  • 1980-1990s: Major outbreaks affected numerous countries, particularly the UK, leading to:

    • Decreased beef consumption, exports, and prices.

    • Legislative changes in feed policies that have since minimized BSE occurrences.

Variant Creutzfeldt-Jakob Disease (vCJD)

  • Pathway of Transmission: Consumption of infected cattle can lead to vCJD, a human counterpart to BSE.

Creutzfeldt-Jakob Disease (CJD)

  • Description: Rapidly progressive neurodegenerative disorder leading to death typically within a year of symptom onset.

  • Early Symptoms: Cognitive decline, behavioral changes, poor coordination, and visual disturbances.

  • Other Symptoms: Depression, mood fluctuation, anxiety, and insomnia are common.

  • Causes: Unknown in most cases; some hereditary components and exposure-related cases exist.

  • Prevalence: Approximately 1-2 cases per million in the US.

Kuru

  • Definition: Infectious prion disease historically prevalent among the Fore people of Papua New Guinea, known for causing uncontrollable laughter due to neural damage.

  • Incubation Period: Typically 10-13 years, but can extend to 50 years.

  • Stages of Disease:

    • Ambulant Stage: Unsteady gait and tremors.

    • Sedentary Stage: Inability to walk without assistance.

    • Terminal Stage: Bedridden state with severe decline.

  • Transmission: Linked to funerary cannibalism where familial remains were consumed.

  • Epidemiology: Last reported case occurred between 2005 and 2009, following the cessation of cannibalistic practices in the 1960s.

Prion-Like Diseases

  • Definition: A classification of several neurodegenerative diseases sharing characteristics with prion diseases, including:

    • Multiple System Atrophy (MSA).

    • Alzheimer’s Disease.

    • Parkinson’s Disease.

    • Amyotrophic Lateral Sclerosis (ALS).

  • Transmission Mechanisms:

    • Evidence indicates potential transmissibility of Alzheimer’s disease under specific conditions, particularly linked to prion-like protein interactions.

  • Prion Protein Interaction: PrPC can aggregate with amyloid-beta, a common protein finding in Alzheimer’s disease, indicating similar propagation methods as in classical prion diseases.