Background

Staphylococcus aureus is the dominant infective trigger of atopic dermatitis (AD). How this bacterium drives type 2 allergic pathology in the absence of infection in patients with AD is unclear.

Objective

We sought to identify the S aureus–derived virulence factor(s) that initiates the cutaneous type 2–promoting immune response responsible for AD.

Methods

In vitro human keratinocyte cell culture, ex vivo human skin organ explants, and the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse were used as model systems to assess type 2–promoting immune responses to S aureus. Identification of the bioactive factor was accomplished using fast protein liquid chromatography and mass spectrometry. Bioactivity was confirmed by cloning and expression in an Escherichia coli vector system, and S aureus second immunoglobulin-binding protein (Sbi) mutant strains confirming loss of activity.

Results

S aureus was unique among staphylococcal species in its ability to induce the rapid release of constitutive IL-33 from human keratinocytes independent of the Toll-like receptor pathway. Using the eczema-prone Nishiki-nezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse model, we showed that IL-33 was essential for inducing the immune response to S aureus in vivo. By fractionation and candidate testing, we identified Sbi as the predominant staphylococcus-derived virulence factor that directly drives IL-33 release from human keratinocytes. Immunohistology of skin demonstrated that corneodesmosin, a component of corneodesmosomes that form key intercellular adhesive structures in the stratum corneum, was disrupted, resulting in reduction of skin barrier function.

Conclusions

S aureus–derived Sbi is a unique type 2–promoting virulence factor capable of initiating the type 2–promoting cytokine activity underlying AD.

中文翻译：

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金黄色葡萄球菌第二免疫球蛋白结合蛋白通过 IL-33 驱动特应性皮炎

背景

金黄色葡萄球菌是特应性皮炎 (AD) 的主要感染诱因。在 AD 患者没有感染的情况下，这种细菌如何驱动 2 型过敏病理尚不清楚。

客观的

我们试图确定金黄色葡萄球菌衍生的毒力因子，其启动负责 AD 的皮肤 2 型免疫反应。

方法

体外人角质形成细胞培养、离体人皮肤器官外植体和易患湿疹的 Nishiki-nezumi Cinnamon/东京农业科技大学品系小鼠被用作模型系统，以评估对金黄色葡萄球菌的2 型促进免疫反应。使用快速蛋白质液相色谱法和质谱法完成生物活性因子的鉴定。生物活性通过在大肠杆菌载体系统中的克隆和表达得到证实，金黄色葡萄球菌第二免疫球蛋白结合蛋白 (Sbi) 突变株证实活性丧失。

结果

金黄色葡萄球菌在葡萄球菌物种中是独一无二的，因为它能够独立于 Toll 样受体通路诱导人角质形成细胞快速释放组成型 IL-33。使用易患湿疹的 Nishiki-nezumi Cinnamon/东京农业技术大学品系小鼠模型，我们发现 IL-33 对诱导体内对金黄色葡萄球菌的免疫反应至关重要。通过分级分离和候选测试，我们确定 Sbi 是主要的葡萄球菌衍生毒力因子，可直接驱动人角质形成细胞释放 IL-33。皮肤的免疫组织学表明，角质层蛋白是角质层中形成关键细胞间粘附结构的角质层的一种成分，被破坏，导致皮肤屏障功能降低。

结论

金黄色葡萄球菌衍生的 Sbi 是一种独特的 2 型促进毒力因子，能够启动 AD 背后的 2 型促进细胞因子活性。