Poxvirus

UCDAVIS HEALTH Poxviruses

Course Information

• Course Code: MMI 177

• Semester: Winter 2025

• Instructor: Loubna Tazi, Ph.D.

• Department: Medical Microbiology & Immunology, UC Davis, School of Medicine

Contact Information

• Phone: 392-2977

Outline of Key Topics

1. Taxonomy of poxviruses (orthopoxviruses).

2. Clinical course of variola infection.

3. Virion morphology and poxvirus genomes.

4. Poxvirus replication cycle.

5. Eradication of smallpox.

Learning Objectives

Upon completion of this chapter, students should be able to:

1. Outline the taxonomy of poxviruses, particularly the orthopoxviruses that infect humans.

2. Describe the clinical course of variola infection, the stages of the smallpox rash, and the four major clinical presentations of variola major.

3. Explain the morphological features of the virion and genome of the vaccinia virus.

4. Outline how the vaccinia virus accomplishes each stage of the viral replication cycle, pointing out notable viral proteins involved in the process.

5. Recall how smallpox was eradicated, beginning with Edward Jenner’s vaccination and ending with the last natural case of infection.

Poxviruses with Major Public Health Significance

Variola Virus (Smallpox)

• Host Range: Very narrow (Humans)

• Virulence: Highly virulent (up to 30% fatality rate)

• Achievement: First virus to be eradicated.

Vaccinia Virus (Vaccination)

• Host Range: Very broad.

• Disease: Mild in humans.

• Role: Successful vaccine against smallpox, facilitating its eradication.

• Research: Intensively studied poxvirus.

Monkeypox Virus

• Host Range: Very broad.

• Disease: Contagious and zoonotic (African gophers and rodents as reservoirs).

• Relevance: Recent global outbreak.

Myxoma Virus (Myxomatosis)

• Host Range: Narrow (rabbits and hares).

• Virulence: Non-virulent in wild rabbits, highly virulent (99.8% fatality rate) in European rabbits.

• Application: Studies of host-virus coevolution.

Taxonomy of Poxviruses

• Family: Poxviridae

Subfamilies

1. Entomopoxvirinae (invertebrates)

   • Includes 4 genera and over 31 species.

2. Chordopoxvirinae (vertebrates)

   • Includes 18 genera and over 64 species.

   • Example: Orthopoxvirus

     • Divided into "Old World" and "New World" strains.

General Characteristics of Poxviruses

• Pathogenicity: Significant human and animal pathogens.

• Genome Structure: Double-stranded DNA, large in size.

• Replication: Occurs exclusively in the cytoplasm; does not require host nucleus.

• Entry Mechanism: Independent of specific host-cell receptors.

• Replication Strategy: Subversion of innate immune response and inhibition of host cell signaling pathways.

• Host Range: Many poxviruses, like vaccinia and monkeypox, exhibit broad host ranges.

• Significance: First scientifically verified vaccine was for vaccinia virus; used for vaccine development and experimental cancer therapies.

Selected Orthopoxviruses Overview

Morphological Features of Poxvirus Virions

• Basic Structure: Enveloped and brick-shaped viruses.

• Size: Largest mammalian viruses, approximately 350 nm by 250 nm.

• Genome: Large linear double-stranded DNA genomes ranging from 135 – 486 kb, encoding approximately 200 (up to 392) genes.

• Genomic Organization:

  • Contains inverted terminal repeats (ITRs).

  • Highly conserved regions in the central genome essential for replication and assembly.

  • Variable terminal regions that have genes affecting virulence and host range.

  • Genome replication occurs in the cytoplasm rather than in the nucleus.

• Transcription:

  • Partially overlapping, leading to the formation of double-stranded RNA (dsRNA) as a danger signal.

  • Around half of the genes are important for basic replication, while the other half modulates the host immune response with several identified as host range factors.

Clinical Course of Variola Infection (Smallpox)

General Characteristics

• Causative Agent: Variola virus (VARV).

• Lethality: Considered one of the most deadly diseases in human history with a lethality rate between 10% to 30%.

• Historical Impact: More deaths than all other infectious diseases combined; significant mortality noted in Europe during the 18th century (over 400,000 deaths annually).

Forms of Variola Virus

1. Variola Major:

   • More severe and common type; fatality rate approximately 30%.

2. Variola Minor (Alastrim):

   • Less severe and less common; fatality rate of 1% or less.

Symptoms & Clinical Presentation

• Incubation Period: Asymptomatic period with virus replication starting and spreading to lymph nodes (Day 3-4).

• Onset of Symptoms: Sudden onset, including fever, headache, backache, chills, vomiting, pharyngitis, delirium, and abdominal pain (Table of observed symptoms).

• Rash Progression:

  • Maculopapular rash emerges which progresses through defined stages:

  1. Macules: Red flat spots (Day 1).

  2. Papules: Raised bumps (Day 2).

  3. Vesicles: Filled with opalescent fluid (Days 3-4).

  4. Pustules: Deep-seated pus-filled lesions (Day 7).

• Rash distribution:

  • Centrifugal Pattern: Concentration of lesions on extremities and face (characteristic of smallpox).

  • Centripetal Pattern: Opposite distribution pattern, typical of chickenpox.

• Clinical Presentations:

  1. Ordinary Smallpox: 90% of cases in unvaccinated individuals; characterized by classic symptoms.

  2. Modified Smallpox: Mild form in vaccinated individuals; less severe symptoms.

  3. Flat (Malignant) Smallpox: Rare and characterized by soft lesions that don't develop into pustules; fatality rate >90%.

  4. Hemorrhagic Smallpox: Rare with widespread bleeding, fatality rate >98%.

Smallpox Transmission

• Primary Host: Humans are the only natural hosts for variola virus.

• Transmission Routes:

  • Airborne (via upper respiratory tract).

  • Direct contact with respiratory droplets, bodily fluids or fomites.

• Infectivity: 90% of aerosolized virus inactivated within 24 hours; remains infectious in scabs for years.

Smallpox Vaccine and Eradication

• Edward Jenner's Contribution: Developed the smallpox vaccine in 1796 using cowpox virus.

• Modern Timeline of Vaccination:

  • 20th century: Up to 500 million deaths due to smallpox.

  • 1979: WHO certified eradication of smallpox globally.

Complications and Cessation of Vaccination

• Complications of Vaccination: 1. Inadvertent autoinoculation, 2. Generalized vaccinia, 3. Postvaccinial encephalitis, 4. Progressive vaccinia, and 5. Eczema vaccinatum.

• Cessation in Vaccinations: 1980 WHO recommended cessation of vaccinations due to lack of endemicity and associated risks.

• Risks of Reemergence: Concerns over the potential use of smallpox as a biological weapon and reemergence from preserved stocks.

Myxomatosis and Other Poxviruses

Myxoma Virus

• Introduction: Used as a biological control in European rabbit populations.

• Impact: Lead to severe population declines and changes in ecosystems.

Monkeypox Virus

• Characteristics: Zoonotic disease, with a broad host range, and significant recent outbreaks.

• Symptoms: Clinically similar to smallpox but includes lymphadenopathy; vaccination with vaccinia virus provides protection.

Historical Perspective and Outbreaks

• Key Notable Outbreaks: 2018-2021 UK monkeypox cases, 2022 US outbreak initiated from imported rodents.

• 2022/2023 Global Trends: Notable mpox outbreak, with significant infection rates and continued monitoring of new variants.