Exfoliative toxin A and desmosomal adhesion in epidermis

描述（由申请人提供）：金黄色葡萄球菌分泌的剥脱毒素A（ETA）可导致大疱性脓疱病和葡萄球菌烫伤样皮肤综合征（SSSS）患者表皮的破坏，使患者容易受到危及生命的感染和脱水。桥粒对于耐受应力的组织（例如表皮）中的细胞：细胞粘附至关重要。这些蛋白质复合物将中间丝锚在细胞连接处，为皮肤提供必要的机械强度，作为身体抵御环境侵害的第一道防线。以前的工作表明，ETA切割桥粒芯糖蛋白1（Dsg1），桥粒组分和表浅表皮的主要钙粘蛋白。拟议的研究将确定ETA切割Dsg1导致SSSS的特定分子后果。特别是，毒素对桥粒组分的运输和相互作用的影响将作为降低角质形成细胞粘附的机制进行研究;此外，诱饵Dsg1胞外域将作为体外和表皮等同物中的ETA抑制剂进行评估。结果将提供一个更完整的了解SSSS发病机制，并将确定新的治疗靶点治疗毒素介导的疾病。

DESCRIPTION (provided by applicant): Exfoliative toxin A (ETA) secreted by Staphylococcus aureus causes destruction of human epidermis in bullous impetigo and Staphylcoccal Scalded Skin Syndrome (SSSS), which renders victims vulnerable to life-threatening infections and dehydration. Desmosomes are crucial for cell:cell adhesion in tissues enduring stress, such as the epidermis. These protein complexes anchor intermediate filaments to celhcell junctions, providing the mechanical strength necessary for the skin to serve as the body's first line of defense against environmental insults. Previous work has shown that ETA cleaves desmoglein 1 (Dsg1), a desmosome component and the predominant cadherin of the superficial epidermis. The proposed research will determine the specific molecular consequences of Dsg1 cleavage by ETA that contribute to SSSS. In particular, the toxin's effects on trafficking of and interactions among desmosomal components will be investigated as mechanisms reducing adhesion in keratinocytes; as well, a decoy Dsg1 ectodomain will be evaluated as an ETA inhibitor in vitro and in epidermal equivalents. The results will provide a more complete understanding of SSSS pathogenesis and will identify novel therapeutic targets for treatment of a toxin-mediated disease.