Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation

PLoS Pathog. 2012;8(8):e1002841. doi: 10.1371/journal.ppat.1002841. Epub 2012 Aug 16.

Abstract

Intracellular Toll-like receptors (TLRs) expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV), a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP) deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8(+) T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Endopeptidases / genetics
  • Endopeptidases / immunology*
  • Endopeptidases / metabolism
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza A Virus, H1N1 Subtype / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology*
  • Toll-Like Receptor 7 / metabolism

Substances

  • Membrane Glycoproteins
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Endopeptidases

Grant support

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was supported by grants from INSERM (ANR 2010 MIDI 008 01 to B. M and ANR 2008 NKTVir to M. S), an ARC PhD fellowship to S. M, an Institut Curie Ph.D. fellowship to M. T, FRM and ANR post-doc support respectively to S. H and D. D.