Host Immune Response to West Nile Virus


Innate Immune Response

1) Interferons

A) Type I (IFN-α and IFN-)

  • Produced by most cell types following virus infection
  • Induces an antiviral state by upregulating genes with direct and indirect antiviral functions
  • Links innate and adaptive immune responses through stimulation of dendritic-cell maturation
  • Direct activation of B- and T-cells
  • Prevent death of recently activated T cells
  • Pretreatment with IFN-α/ inhibits WNV replication in vitro, but treatment after infection is much less effective
  • Although WNV can directly antagonize IFN-induced responses after infection, type I IFN is still required to restrict WNV replication and spread
  • Found that the lack of IFN-α/ receptors (IFN-α/R) resulted in uncontrolled viral replication, rapid dissemination to the CNS, and enhanced lethality
  • Altered viral tropism and enhanced infection also seen in IFN-α/R-/- mice in normally resistant cell populations and peripheral tissues

    B) Type II (IFN-γ)

  • Produced by γδ T-cells, CD8+ T-cells, and natural killer (NK)
  • Restricts viral replication directly by:
  • WNV is also resistant to the antiviral effects of IFN-γ after infection in vitro
  • It was found in vivo that IFN-γ limits early viral dissemination to the CNS
  • Mice deficient in either IFN-γ or the IFN-γ receptor showed greater peripheral viral burden and earlier entry into the CNS

    B) Type III (IFN-λ)

    2) Viral Sensors and IFN-induced Effector Molecules

  • Cells recognize and respond to RNA virus infection through several nucleic acid sensors:
  • Activation of pathogen recognition receptors stimulates IFN production, which induces feedback amplification of the IFN-stimulated gene response

    3) Complement

  • Pathogen recognition and clearance
  • Host protection through direct opsonization and/or cytolysis, chemotaxis, immune clearance, and modulation of B- and T-cell functions
  • Required for protection from lethal WNV infection in mice after activation
  • All three pathways of complement activation are important for controlling WNV

    4) Cellular Innate Immunity

  • Limited data suggest that macrophages and dendritic cells may directly inhibit WNV
  • Macrophage uptake of WNV could control infection through direct viral clearance, enhanced antigen presentation, and cytokine/chemokine secretion
  • γδ T-cells also function in early immune responses by directly limiting WNV infection
  • Viruses may have developed a mechanism to inhibit NK cells early recognition and elimination of virus-infected cells
  • WNV infection in vitro increases surface MHC-I expression in some cell types by enhancing the activity of the transporter associated with antigen processing and by NF-κB-dependent transcriptional activation of MHC class I genes

    Adaptive Immune Response

    1) Humoral Response

  • Aspect of immune system-mediated protection from WNV
  • B-cell deficient mice died after WNV infection, but were protected by passive transfer of immune sera
  • Soluble IgM is important in protection against WNV
  • IgG can protect against flavivirus infection, but its function during primary infection is less clear (production 4-6 days after infection)

    Mechanisms of Antibody Protection

  • Majority of neutralizing antibodies are directed against regions of the WNV envelope (E) protein
  • Subset likely recognizes the prM protein

    Envelope (E) protein and Neutralizing Antibody

  • Three structural domains that mediate viral attachment, entry, and viral assembly
  • Antibodies against these structural domains have distinct neutralization potentials.
  • Most potent inhibitory antibodies recognize a dominant neutralizing epitope on the lateral face of DIII

    Non-structural proteins and Neutralizing Antibody

  • Antibodies to the nonstructural protein NS1
  • NS1 may inhibit complement activation by binding regulatory protein factor H

    2) T-cell Responses during Primary Infection

  • Hematologic malignancies and impaired T-cell function have an increased risk of neuroinvasive WNV infection
  • T-cell recognize WNV infected cell that expresses class I MHC molecules → antigen-restricted cytotoxic T-cell proliferates and release pro-inflammatory cytokines → lyse infected cells directly through the delivery of perforin and granzymes A and B or via Fas-Fas ligand interactions

    3) Memory Response

  • Humoral and cellular responses likely essential for protection
  • T-cellmediated immunity is also likely necessary to resist subsequent WNV challenge
  • γδ T-cells contribute directly to priming protective adaptive immune responses to WNV

    CNS Immune Response to WNV

  • After peripheral inoculation, virus spreads to the CNS
  • CNS requires clearance of virus with limited damage to critical non-renewing cells such as neurons
  • IFN-α/ controls WNV replication in neurons → modulating survival
  • CD8+ T-cells traffic to the brain after WNV infection in mice → temporally aid with viral clearance
  • Chemokine-dependent T-cell recruited to infected CNS tissues α

    Citation:
    Hayes, EB. et al. (2005) Virology, pathology, and clinical manifestations of West Nile Virus disease. Emerg Infect Dis. 11(8):1174-9.

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