A Staphylococcus Aureus TIR Domain Protein Virulence Factor Blocks TLR2-mediated NF-κB Signaling

J Innate Immun. 2014;6(4):485-98. doi: 10.1159/000357618. Epub 2014 Jan 25.

Abstract

Signaling through Toll-like receptors (TLRs), crucial molecules in the induction of host defense responses, requires adaptor proteins that contain a Toll/interleukin-1 receptor (TIR) domain. The pathogen Staphylococcus aureus produces several innate immune-evasion molecules that interfere with the host's innate immune response. A database search analysis suggested the presence of a gene encoding a homologue of the human TIR domain in S. aureus MSSA476 which was named staphylococcal TIR domain protein (TirS). Ectopic expression of TirS in human embryonic kidney, macrophage and keratinocyte cell lines interfered with signaling through TLR2, including MyD88 and TIRAP, NF-κB and/or mitogen-activated protein kinase pathways. Moreover, the presence of TirS reduced the levels of cytokines MCP-1 and G-CSF secreted in response to S. aureus. The effects on NF-κB pathway were confirmed using S. aureus MSSA476 wild type, an isogenic mutant MSSA476ΔtirS, and complemented MSSA476ΔtirS +pTirS in a Transwell system where bacteria and host cells were physically separated. Finally, in a systematic mouse infection model, TirS promoted bacterial accumulation in several organs 4 days postinfection. The results of this study reveal a new S. aureus virulence factor that can interfere with PAMP-induced innate immune signaling in vitro and bacterial survival in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Amino Acid Sequence
  • Animals
  • Bacterial Load / genetics
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Line
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Female
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Humans
  • Immune Evasion
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism*
  • Receptors, Interleukin-1 / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics
  • Staphylococcal Infections / immunology*
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / immunology*
  • Staphylococcus aureus / pathogenicity
  • Toll-Like Receptor 2 / metabolism*
  • Virulence Factors / genetics

Substances

  • Adaptor Proteins, Vesicular Transport
  • Bacterial Proteins
  • CCL2 protein, human
  • Chemokine CCL2
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Receptors, Interleukin-1
  • TICAM1 protein, human
  • TIR domain protein, Staphylococcus aureus
  • TIRAP protein, human
  • Toll-Like Receptor 2
  • Virulence Factors
  • Granulocyte Colony-Stimulating Factor