YjbH contributes to <i>Staphylococcus aureus</i> skin pathology and immune response through Agr-mediated α-toxin regulation

<i>Staphylococcus aureus</i> is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant <i>S. aureus</i> (MRSA) strains being a major contributor in both community and hospital settings. <i>S. aureus</i> relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both <i>in vitro</i> and <i>in vivo</i>. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the Δ<i>yjbIH</i> mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the Δ<i>yjbH</i> mutant. This work continues to define the importance of YjbH in the pathogenesis of <i>S. aureus</i> infection as well as identify a new pathway important for Hla production.

金黄色葡萄球菌（Staphylococcus aureus）是皮肤和软组织感染（skin and soft tissue infections, SSTIs）最常见的致病菌，耐甲氧西林金黄色葡萄球菌（Methicillin-Resistant S. aureus, MRSA）菌株则是社区与医院环境中感染的主要致病源。金黄色葡萄球菌依赖代谢多样性与丰富的毒力因子组引发疾病，其中包括α-溶血素（α-hemolysin, Hla）——该因子是介导组织损伤的核心组分，在包括SSTIs在内的多种感染模型中均发挥关键作用。此前本团队已证实，Spx接头蛋白YjbH可调控多种毒力因子的表达，并在败血症模型中作为致病过程的抑制剂。本研究发现，YjbH对SSTIs过程中的组织损伤至关重要；缺失YjbH会导致皮肤组织中促炎性趋化因子与细胞因子水平降低。我们未发现与YjbH共享同一转录本的YjbI存在相关致病贡献。通过结合报告基因检测与定量溶血实验，我们证实YjbH可在体外（in vitro）与体内（in vivo）环境中影响α-溶血素的表达与活性。此外，通过非天然启动子表达α-溶血素，可逆转ΔyjbIH突变株的组织损伤表型。最后，我们发现附属基因调节因子（accessory gene regulator, Agr）活性下调，可能是ΔyjbH突变株中α-溶血素生成减少的潜在原因。本研究进一步明确了YjbH在金黄色葡萄球菌感染致病过程中的重要性，并鉴定出一条调控α-溶血素生成的全新通路。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于金黄色葡萄球菌皮肤感染的研究，具体探讨YjbH蛋白如何通过调节Agr系统影响α-毒素（Hla）的产生，从而在皮肤病理和免疫响应中发挥关键作用。数据集包含实验数据，支持YjbH缺失导致组织损伤减少和炎症因子降低的发现，揭示了新的Hla产生途径，为理解金黄色葡萄球菌的致病机制提供了重要见解。