期刊
JOURNAL OF INNATE IMMUNITY
卷 6, 期 4, 页码 485-498出版社
KARGER
DOI: 10.1159/000357618
关键词
Staphylococcus aureus; Staphylococcal TIR domain protein; TirS; TLR signaling; Mitogen-activated protein kinase; NF-KB; Bacterial TIR domain
类别
资金
- Research Council of Norway [191264/V50]
- Northern Norway Regional Health Authority (Helse Nord RHF)
- Toppforskning [SFP877-09]
- Miljostotte [MIL963-10]
- NIH/NIAID/ GLRCE research grant [A1057153]
- Marie Curie International Incoming Fellowship
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-KB 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-KB pathway were confirmed using S. aureus MSS Delta 476 wild type, an isogenic mutant MSS Delta 476AtirS, and complemented MSS Delta 476AtirS +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. (c) 2014 S. Karger AG, Basel
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