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脱落毒素A(ETA)会在大疱性脓疱病和葡萄球菌烫伤皮肤综合征(SSSS)中破坏人的表皮，使患者容易受到危及生命的感染和脱水。桥粒对细胞至关重要：细胞黏附在承受压力的组织中，如表皮。这些蛋白质复合体将中间细丝锚定在细胞连接上，为皮肤提供必要的机械强度，作为人体抵御环境侮辱的第一道防线。先前的研究表明，ETA能裂解桥粒蛋白1(DSG1)，它是一种桥粒成分，也是浅层表皮的主要钙粘附素。这项拟议的研究将确定DSG1被ETA切割的特定分子后果，这些结果有助于SSSS。特别是，毒素对桥粒成分的运输和相互作用的影响将作为减少角质形成细胞黏附的机制进行研究；此外，诱骗DSG1胞外结构域将在体外和表皮等效物中作为ETA抑制剂进行评估。这一结果将提供对SSSS发病机制的更完整的了解，并将确定治疗毒素介导的疾病的新的治疗靶点。

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.