Activation of Nrf2 by the dengue virus causes an increase in CLEC5A, which enhances TNF-α production by mononuclear phagocytes

Sci Rep. 2016 Aug 26:6:32000. doi: 10.1038/srep32000.

Abstract

Infection by the dengue virus (DENV) threatens global public health due to its high prevalence and the lack of effective treatments. Host factors may contribute to the pathogenesis of DENV; herein, we investigated the role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is activated by DENV in mononuclear phagocytes. DENV infection selectively activates Nrf2 following nuclear translocation. Following endoplasmic reticular (ER) stress, protein kinase R-like ER kinase (PERK) facilitated Nrf2-mediated transcriptional activation of C-type lectin domain family 5, member A (CLEC5A) to increase CLEC5A expression. Signaling downstream of the Nrf2-CLEC5A interaction enhances Toll-like receptor 3 (TLR3)-independent tumor necrosis factor (TNF)-α production following DENV infection. Forced expression of the NS2B3 viral protein induces Nrf2 nuclear translocation/activation and CLEC5A expression which increases DENV-induced TNF-α production. Animal studies confirmed Nrf2-induced CLEC5A and TNF-α in brains of DENV-infected mice. These results demonstrate that DENV infection causes Nrf2-regulated TNF-α production by increasing levels of CLEC5A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cricetinae
  • Dengue Virus / physiology*
  • Humans
  • Lectins, C-Type / metabolism*
  • Mice
  • Monocytes / metabolism
  • Monocytes / virology*
  • NF-E2-Related Factor 2 / physiology*
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 3 / metabolism
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism

Substances

  • CLEC5A protein, human
  • Clec5a protein, mouse
  • Lectins, C-Type
  • NF-E2-Related Factor 2
  • Receptors, Cell Surface
  • Toll-Like Receptor 3
  • Tumor Necrosis Factor-alpha
  • Viral Nonstructural Proteins