Lecture 11

Yellow Fever

What is Yellow Fever?

  • Definition: Yellow fever virus is primarily spread to humans through the bite of infected Aedes species mosquitoes, specifically Aedes aegypti and Aedes albopictus.

  • Symptoms: Many infected individuals show no symptoms or experience only mild, flu-like symptoms.

Serious Illness

  • About 15% of infected individuals develop severe illness, which can be fatal.

  • Of those who progress to severe illness, approximately 50% die within 7 to 10 days post-infection.

Geographic Risk

  • Travelers to certain parts of South America and Africa are at risk for yellow fever; consult the CDC webpage for specific regions.

  • For example:

    • In 2015, Angola reported 1975 suspected cases and 258 deaths.

Vaccination

  • The yellow fever vaccine is the most effective preventative measure against the disease.

  • More details can be found on the CDC's webpage: CDC Yellow Fever Information.

Systemic Pathogenesis of Yellow Fever Virus

  • Key Structures Affected:

    • Liver: Release of liver enzymes, macrophage dysfunction leading to immune system dysregulation, and excess cytokines.

    • Kidneys/Adrenal Gland: Production of clotting factors is disrupted, affecting blood pressure regulation.

    • Immune System: Aberrant maturation of immune cells and impaired T cell activation, leading to apoptosis of lymphocytes.

    • Circulatory System: Leakage and coagulopathy cause low blood pressure and damage to the endothelium.

    • Complications can lead to viral hemorrhagic fever.

Systemic Spread of Yellow Fever

Symptoms of Yellow Fever

  • Incubation Period: 3-6 days

  • Symptoms may include:

    • Jaundice (yellow eyes)

    • Headache

    • Backache

    • Vomiting

    • Bleeding

  • Mortality: Death can occur between day 7 and 10 of illness.

  • In about 15% of cases, the disease may progress to severe forms with symptoms such as fever, jaundice, renal failure, and hemorrhaging.

Transmission Cycles

  • Sylvatic Cycle: Involves wild monkey populations and forest mosquitoes.

  • Urban Cycle: Involves Aedes aegypti mosquitoes that have adapted to urban environments.

Yellow Fever Virus Transmission

Yellow Fever Virus Characteristics

  • First Isolated: 1927

  • Family: Flaviviridae

  • Genus: Flavivirus (related to dengue, Zika, Japanese encephalitis, and West Nile viruses)

  • Structure:

    • Icosahedral, enveloped

    • Genome: Non-segmented +ssRNA of approximately 10-11 kb.

Viral Structure

  • Proteins:

    • M Protein

    • E Dimer

    • C Protein

  • Genomic RNA: Methylated nucleotide cap is present at the 5' end for cellular translation into one polyprotein, whereas the 3' end forms a stem-loop structure.

  • Contains three structural proteins and seven non-structural proteins.

Viral Structure

Flavivirus Replication

  1. Internalization: The viral envelope (E protein) attaches to host receptors and mediates internalization through clathrin-mediated endocytosis.

  2. Membrane Fusion: Viral membrane fuses with the host endosomal membrane.

  3. RNA Release: The (+) RNA genome is released into the host cell.

  4. Protein Translation: The (+) genomic RNA is translated into a polyprotein, which is processed into 3 structural and 7 non-structural proteins.

  5. RNA Synthesis: The (-) RNA is synthesized from the (+) genomic RNA, and transcribed to replicate viral mRNAs and new ssRNA(+) genomes.

  6. Assembly: Virus assembly occurs at the Endoplasmic Reticulum (ER).

  7. Maturation: The prM protein is cleaved in the Golgi for maturation.

  8. Release: New virions are released by exocytosis.

Historical Overview

  • 3000 B.C.E: Yellow fever is believed to have evolved in Africa.

  • 1600s: Yellow fever was brought to the Western Hemisphere via slave ships from West Africa. The first evidence of yellow fever in the Americas appeared in Mayan texts describing outbreaks.

  • 1800s: Misconceptions existed regarding transmission until late 19th century theories suggested mosquitoes as the vector.

  • 1900s: The Reed Yellow Fever Commission confirmed mosquito transmission in 1900, leading to successful mosquito control strategies by 1902.

Diagnosis and Prevention

  • Diagnosis: Involves laboratory testing of serum to detect virus-specific IgM and neutralizing antibodies using techniques like ELISA and PRNT. Real-time PCR is also used in early detection.

  • Prevention:

    • Insect Repellents: DEET, picaridin, or oil of lemon eucalyptus should be used.

    • Protective Clothing: Long-sleeved shirts and pants are advisable.

    • Vaccination:

    • The yellow fever vaccine is a live attenuated virus vaccine (17D strain), offering lifelong protection after a single dose.

    • Vaccination is recommended for individuals traveling to endemic areas and should be done at least 10 days before travel.

    • The vaccine is available through specific clinics in the United States and confirmed with a "yellow card," recognized internationally.

Yellow Fever Vaccination Information

Treatment

  • Palliative Care: Hospitalization is recommended for observation.

  • Supportive Care: Involves:

    • Fluid administration

    • Oxygen support

    • Blood pressure maintenance

    • Blood transfusions for clotting factors

    • Dialysis for kidney failure

  • Avoidance of NSAIDs and Aspirin: These may increase bleeding risks.

  • Recovery: Once an individual recovers from yellow fever, they gain lifelong immunity.

Hepatitis C Virus (HCV) Overview

  • Genome Discovery: First reported in 1989, it belongs to the family Flaviviridae and has significant structural and replication similarities to yellow fever virus.

  • Progression: Approximately 85% of infections lead to chronic liver diseases.

  • Treatment Advances: Combination drugs targeting NS5a, NS5b, NS3/4A have been developed, though they are prohibitively expensive.

  • Vaccination: There is no vaccine currently available for HCV.