Antibody-dependent enhancement of dengue virus infection inhibits RLR-mediated Type-I IFN-independent signalling through upregulation of cellular autophagy

Sci Rep. 2016 Feb 29:6:22303. doi: 10.1038/srep22303.

Abstract

Antibody dependent enhancement (ADE) of dengue virus (DENV) infection is identified as the main risk factor of severe Dengue diseases. Through opsonization by subneutralizing or non-neutralizing antibodies, DENV infection suppresses innate cell immunity to facilitate viral replication. However, it is largely unknown whether suppression of type-I IFN is necessary for a successful ADE infection. Here, we report that both DENV and DENV-ADE infection induce an early ISG (NOS2) expression through RLR-MAVS signalling axis independent of the IFNs signaling. Besides, DENV-ADE suppress this early antiviral response through increased autophagy formation rather than induction of IL-10 secretion. The early induced autophagic proteins ATG5-ATG12 participate in suppression of MAVS mediated ISGs induction. Our findings suggest a mechanism for DENV to evade the early antiviral response before IFN signalling activation. Altogether, these results add knowledge about the complexity of ADE infection and contribute further to research on therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology*
  • Autophagy
  • Cell Line
  • DEAD Box Protein 58 / metabolism
  • Dengue / immunology*
  • Dengue / metabolism*
  • Dengue / virology
  • Dengue Virus / physiology*
  • Gene Expression
  • Humans
  • Immunity, Innate
  • Interferon Type I / metabolism*
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Interleukin-10 / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Nitriles
  • Pyrrolidines
  • RNA, Viral / biosynthesis
  • Receptors, Immunologic
  • Signal Transduction*
  • Toll-Like Receptors / metabolism*
  • Up-Regulation
  • Viral Load
  • Virus Replication

Substances

  • (S)-1-(4-methyl-1-(2-pyrimidinyl)-4-piperidylamino)acetyl-2-pyrrolidinecarbonitrile
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Interferon Type I
  • Nitriles
  • Pyrrolidines
  • RNA, Viral
  • Receptors, Immunologic
  • Toll-Like Receptors
  • Interleukin-10
  • Nitric Oxide Synthase Type II
  • RIGI protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1