Cardiotoxicity of Streptococcal Pyrogenic Exotoxins

描述（由申请人提供）：该项目的长期目标是 两方面：a）评价热原毒素超抗原的作用，特别是 链球菌致热性外毒素（SPE，猩红热毒素，在引起 急性中毒性休克综合征和血管疾病和慢性自身免疫性疾病， 过敏性疾病，和B）分析结构： SPEs和SPEs与葡萄球菌肠毒素和毒性之间的关系 休克综合征毒素-1，目的是阐明分子机制 研究毒素的作用，开发类毒素疫苗， 毒素的佐剂。 本申请的具体目的包括： SPEs J和L的免疫生物学表征，并确定三种 两种毒素的三维结构（SPE与 T细胞受体β链可变部分和主要 组织相容性复合物II分子将被确定，如果这样的结构 可能会产生新的数据）。我们在这一目标中的作用将是描述 新的SPE，为结构研究提供毒素， 用于结晶、制备和测试突变体的条件 用于确认SPE上的重要接触残留物 B）SPE C和可能的SPE J的表征 穿过粘膜表面的能力。研究将包括建立 阴道上皮单层和复层上皮， 评价毒素穿过层的机制。我们将 还评估了生物学上无活性的毒素透化 上皮细胞，在体外和在兔，以其他代理，因此，确定 类毒素是否可用作递送剂（和可能的佐剂） 用于经粘膜免疫;和c）表征 链球菌中毒性休克综合征伴坏死性筋膜炎家兔我们 假设SPE通过以下途径引起低血压和延迟吞噬作用 过度的细胞因子释放，这反过来又允许细胞的持续生长。 通过溶血素产生坏死性筋膜炎的侵袭性微生物 和蛋白酶。

DESCRIPTION (provided by applicant): The long term goals of this project are two fold: a) to evaluate the role of pyrogenic toxin superantigens, notably streptococcal pyrogenic exotoxins (SPEs, scarlet fever toxins, in causing both acute toxic shock syndrome and vascular illnesses and chronic autoimmune and allergic diseases, and b) to analyze the structure:function relationships among the SPEs and between the SPEs and the staphylococcal enterotoxins and toxic shock syndrome toxin-1, with the intent of clarifying the molecular mechanisms of action of the toxins, developing toxoid vaccines, and developing useful adjuvants of the toxins. Specific aims of the present application include: a) Biochemical and immunobiological characterization of SPEs J and L, and determining the three dimensional structure of both toxins (complex structures of the SPEs with the variable part of the beta chain of the T cell receptor and major histocompatibility complex II molecules will be determined if such structures are likely to generate new data). Our role in this aim will be to characterize the new SPEs, provide toxins for structural studies, consult on the best conditions for use in crystallization, and preparation and testing mutant toxins for confirmation that important contact residues on the SPEs are required for activity; b) Characterization of SPE C's, and possibly SPE J's ability to cross mucosal surfaces. Studies will include establishment of vaginal epithelial monolayers and stratified epithelium in Transwells and evaluation of the mechanism by which the toxin(s) traverse the layers. We will also evaluate the ability of biologically inactive toxins to permeabilize the epithelium, both in vitro and in rabbits, to other agents, and thus, determine whether the toxoids may be useful as delivery agents (and possibly adjuvants) for transmucosal immunization; and c) Characterization of the mechanism of streptococcal toxic shock syndrome with necrotizing fasciitis in rabbits. We hypothesize that SPEs cause both hypotension and delayed phagocytosis through exaggerated cytokine release, which in turn allows continued growth of the invasive organism with production of necrotizing fasciitis through hemolysins and protease.