Interaction of flaviviruses with cells of the vertebrate host and decoy of the immune response

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Abstract
Flaviviruses cause endemic and epidemic disease with significant morbidity and mortality throughout the world. In contrast to viruses that avoid the host immune response by down-regulating cell surface major histocompatibility complex expression, infection by members of the neurotropic Japanese encephalitis serogroup induce virus-directed functional increases in expression of class I and II major histocompatibility complex and various adhesion molecules, resulting in increased susceptibility to both virus- and major histocompatibility complex-specific cytotoxic T lymphocyte lysis. These changes are comodulated by T1 and T2 cytokines, as well as by cell cycle position and adherence status at infection. Infected skin dendritic (Langerhans) cells also show increased costimulatory molecule expression and local interleukin-1beta production causes accelerated migration of Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of up-regulation is unclear, but changes are associated with NF-kappaB activation and increased MHC and ICAM-1 gene transcription, independently of interferon or other pro-inflammatory cytokines. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity, self-reactive T cells which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly up-regulate cell surface molecules. A possible side-effect of this might be immunopathology, caused by 'autoimmune' cross-reactive damage of uninfected high major histocompatibility complex and adhesion molecule-expressing cells, with consequent exacerbation of encephalitic disease. Results from a murine model of flavivirus encephalitis developed in this laboratory further suggest that interferon-gamma plays a crucial role in fatal immunopathology.
Funding Information
  • National Health and Medical Research Council