Yellow fever virus

MICROBIOLOGY

• Yellow fever virus (YFV) is the prototype member of the approximately 75 viruses of the Flaviviridae family; "flavus" derives from the Latin word for yellow.
  • Mosquito vector
  • YFV was first isolated in 1927.
• There is 1 serotype with 7 distinct genotypes.
  • South America: 2 genotypes
  • Africa: 5 genotypes
• Single-stranded RNA virus with an 11 kilobase genome composed of 3 parts:[9]
  
  • 5’ non-coding region
  • A single open reading frame (ORF) that encodes 3 structural and 7 non-structural proteins
    • Structural
      • Capsid (C)
      • Membrane (prM)
      • Envelope (E): This is the main structural protein
        • Mediates virus entry into the cell via clathrin-dependent endocytosis
    • Non-Structural (NS): NS1, NA2a, NS2b, NS3, NS4a, NS4b, and NS5 are involved in:
      • RNA replication
      • Post-translational cleavage of the viral polyprotein
  • 3’ non-coding region
• Cell targets
  • The virus is introduced by blood-feeding mosquitoes into the epidermis, where resident dendritic cells (DCs) are the principal target for early virus replication.[10]
    
    • Toll-like receptors (TLRs) on the surface of DC are key in the critical role of sensing microbial stimuli.
    • DCs initiate and modulate the adaptive immune system.
  • DCs carry the virus via lymphatics to draining lymph nodes and subsequently to the bloodstream with eventual dissemination to cells in the liver, spleen, remaining lymph nodes, kidneys, and heart.
• Immune evasion[9]
  • Inhibition of the innate interferon type I response is key.
  • Non-human primate studies have demonstrated down-regulation of 43 genes associated with innate immunity, including:
    • Interferon-gamma receptor-1
    • CD83, a marker of DC maturation
    • TNFSF11: though to induce DCs to stimulate naive T cell proliferation
• Inflammation
  • Pro-inflammatory mediators are significantly higher in patients with fatal illness when compared with survivors[9] including:
    • Tumor necrosis factor-alpha (TNF-α)
    • Interleukin-6 (IL-6)
    • Interleukin-1 receptor antagonist (IL-1RA)
    • Interferon-gamma inducible protein 10 (IP-10)
    • Monocyte chemoattractant protein-1 (MCP-1)
  • Similar findings were seen in rhesus macaques, the animal model for studying many aspects of yellow fever virus infection.