Supplementary Material for: A<b><i> Staphylococcus aureus</i></b> TIR Domain Protein Virulence Factor Blocks TLR2-Mediated NF-κB Signaling

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 <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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<i> S. aureus</i>. The effects on NF-κB pathway were confirmed using <i>S. aureus</i> MSSA476 wild type, an isogenic mutant MSSA476Δ<i>tirS</i>, and complemented MSSA476Δ<i>tirS +</i>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 <i>S. aureus</i> virulence factor that can interfere with PAMP-induced innate immune signaling in vitro and bacterial survival in vivo.

Toll样受体（Toll-like receptors, TLRs）是诱导宿主防御反应的关键分子，其信号转导过程依赖于携带Toll/白介素-1受体（Toll/interleukin-1 receptor, TIR）结构域的衔接蛋白。病原体金黄色葡萄球菌（Staphylococcus aureus）可分泌多种干扰宿主先天免疫应答的先天免疫逃逸分子。数据库检索分析显示，在金黄色葡萄球菌菌株MSSA476中存在一个编码人TIR结构域同源物的基因，该基因被命名为葡萄球菌TIR结构域蛋白（staphylococcal TIR domain protein, TirS）。将TirS异位表达于人胚肾、巨噬细胞及角质形成细胞系后，可干扰以髓系分化因子88（MyD88）、TIR结构域衔接蛋白（TIRAP）、核因子κB（NF-κB）及/或丝裂原活化蛋白激酶通路为下游靶点的TLR2信号转导。此外，TirS的存在可降低金黄色葡萄球菌刺激下宿主细胞分泌的细胞因子单核细胞趋化蛋白-1（MCP-1）与粒细胞集落刺激因子（G-CSF）水平。研究人员通过Transwell共培养系统（该系统可实现细菌与宿主细胞的物理分隔），分别以金黄色葡萄球菌MSSA476野生株、同基因缺失突变株MSSA476ΔtirS及互补株MSSA476ΔtirS +pTirS开展实验，验证了TirS对NF-κB通路的调控作用。最后，在系统性小鼠感染模型中，感染后第4天的检测结果显示，TirS可促进细菌在多个脏器内的定植与累积。本研究结果揭示了一种全新的金黄色葡萄球菌毒力因子，该因子可在体外干扰病原相关分子模式（pathogen-associated molecular pattern, PAMP）诱导的先天免疫信号通路，并在体内提升细菌的存活能力。

搜集汇总

背景与挑战

背景概述

该数据集是研究“金黄色葡萄球菌TIR结构域蛋白毒力因子阻断TLR2介导的NF-κB信号通路”的补充材料，包含图表文件。数据集揭示了金黄色葡萄球菌产生的TirS蛋白作为一种新型毒力因子，通过干扰TLR2信号通路（包括MyD88、TIRAP、NF-κB和MAPK途径）来抑制宿主的先天免疫反应，并在体外细胞实验和体内小鼠感染模型中验证了其促进细菌生存的作用。