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）导致大疱性脓疱病和葡萄球菌烫伤皮肤综合征（SSSS）的人体表皮破坏，使受害者容易受到危及生命的感染和脱水。桥粒对承受压力的组织（如表皮）的细胞粘附起着至关重要的作用。这些蛋白质复合物将中间细丝固定在细胞连接处，为皮肤提供必要的机械强度，作为人体抵御环境损害的第一道防线。先前的研究表明，ETA可切割桥粒蛋白1 (Dsg1)，桥粒蛋白是一种桥粒成分，也是表皮表层的主要钙粘蛋白。该研究将确定ETA切割Dsg1导致SSSS的具体分子后果。特别是，毒素对运输和桥粒组分之间相互作用的影响将作为减少角化细胞粘附的机制进行研究；此外，将在体外和表皮等效物中评估诱骗Dsg1外结构域作为ETA抑制剂的作用。该结果将提供对SSSS发病机制的更完整的理解，并将为治疗毒素介导的疾病确定新的治疗靶点。

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.