Role of Staphylococcus aureus and Host immunity in Allergic Skin Disease

特应性皮炎（AD）是一种慢性炎症性皮肤病，影响15%至30%的儿童 以及工业化国家约5%的成年人。虽然AD的发病机制尚不完全清楚， 据了解，这种疾病被认为是由异常的炎症反应介导的 包括在皮肤屏障功能障碍的情况下产生免疫球蛋白E（IgE）。损失- 编码促进皮肤生长的表皮蛋白的聚丝蛋白基因的功能突变 屏障，是AD发展的强诱发因素。因为AD的一个特点是 改变皮肤屏障，了解中间丝蛋白缺乏增加的机制 对AD的易感性可提供对疾病发病机理的重要见解。肥大细胞 导致IgE介导的过敏性疾病，包括AD。在用IgE和抗原活化后 或微生物刺激时，MC释放其膜结合的胞质颗粒， 在AD发病机制和宿主防御中重要的多种分子的释放 对抗细菌病原体。值得注意的是，超过90%的AD患者被定植有 金黄色葡萄球菌在病变皮肤，而大多数健康人的皮肤没有 藏匿病原体几种葡萄球菌外毒素（SE）可以作为超抗原和/或 AD模型中的抗原。然而，这些SE在疾病发病机制中的作用仍然存在， 不清楚我们已经鉴定出S.金黄色葡萄球菌，属于肽 毒素家族的酚可溶性调制蛋白（PSM），作为一个有效的诱导MC脱粒。δ- 毒素是由毒力Agr产生的酚可溶性调节蛋白家族的成员 群体感应金黄色。重要的是，S。从AD患者中回收的金黄色葡萄球菌分离株 会产生大量δ毒素值得注意的是，皮肤定植与S。金黄色葡萄球菌，但不是突变体 δ-毒素缺乏可促进IgE和IL-4的产生。此外，IgE的增强 在MC缺陷小鼠中，δ-毒素的产生和皮炎被废除，而MC恢复 重组在本申请中，我们提出了三个具体的目标，以了解如何S。金黄色 被包括角质形成细胞在内的皮肤细胞感知，从而诱导皮肤炎症和IgE。 此外，我们建议研究链接S。金黄色葡萄球菌δ-毒素及相关PSM对宿主免疫的影响 调节皮肤炎症的信号通路。了解S。金黄色葡萄球菌δ-毒素和 由Agr群体感应系统调节的相关PSM有助于过敏性皮肤病， 预计将为AD的发病机制和新药物的开发提供重要见解 预防和/或治疗AD的治疗方法。

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15 to 30% of children and ~5% of adults in industrialized countries. Although the pathogenesis of AD is not fully understood, the disease is thought to be mediated by an abnormal inflammatory response including immunoglobulin E (IgE) production in the setting of skin barrier dysfunction. Loss-of- function mutations in the Filaggrin gene encoding an epidermal protein that promotes the skin barrier, are strong predisposing factors for the development of AD. Because a hallmark of AD is an altered skin barrier, understanding of the mechanism by which Filaggrin deficiency increases the susceptibility to AD may provide critical insight into disease pathogenesis. Mast cells (MCs) contribute to IgE-mediated allergic disorders including AD. Upon activation with IgE and antigen or microbial stimuli, MCs release their membrane-bound cytosolic granules leading to the release of multiple molecules that are important in the pathogenesis of AD and host defense against bacterial pathogens. Notably, more than 90% of AD patients are colonized with Staphylococcus aureus in the lesional skin whereas the skin of most healthy individuals do not harbor the pathogen. Several Staphylococcal exotoxins (SEs) can act as superantigens and/or antigens in models of AD. However, the role of these SEs in disease pathogenesis remains unclear. We have identified δ-toxin, a peptide released by S. aureus that belongs to the peptide toxin family of phenol-soluble modulins (PSMs), as a potent inducer of MC degranulation. δ- toxin is a member of the family of phenol-soluble modulins that is produced by the virulence Agr quorum sensing of S. aureus. Importantly, S. aureus isolates recovered from AD patients produce high levels of δ-toxin. Notably, skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted IgE and IL-4 production. Furthermore, enhancement of IgE production and dermatitis by δ-toxin were abrogated in MC-deficient mice and restored by MC reconstitution. In this application, we propose three specific Aims to understand how S. aureus is sensed by skin cells including keratinocytes to induce inflammation and IgE in the skin. Furthermore, we propose studies to link S. aureus δ-toxin and related PSMs to host immune signaling pathways that mediate skin inflammation. Understanding how S. aureus δ-toxin and related PSMs regulated by the Agr quorum sensing system contribute to allergic skin disease is expected to provide critical insight into the pathogenesis of AD and the development of new therapeutic approaches to prevent and/or treat AD.