Cardiotoxicity of Streptococcal Pyrogenic Exotoxins

描述(由申请人提供)：该项目的长期目标是 两个方面：a)评估热原毒素超抗原的作用，特别是 链球菌致热外毒素(SPE，猩红热毒素，在引起这两种疾病中 急性中毒性休克综合征与血管疾病和慢性自身免疫性疾病 过敏性疾病；b)分析结构：功能之间的关系 SPE及其与葡萄球菌肠毒素和毒素之间的关系 休克综合征毒素-1，旨在阐明其分子机制 毒素的作用，开发毒素疫苗，并开发有用的 毒素的佐剂。 本申请的具体目的包括：a)生化和 SPEs J和L的免疫生物学特性及三者的测定 两种毒素的空间结构(SPE与 T细胞受体β链的可变部分和主要 组织相容性复合体II分子将被确定如果这些结构 可能会产生新的数据)。我们在这一目标中的角色将是 新的SPE为结构研究提供毒素，咨询最佳 用于结晶的条件、突变体的制备和检测 确认SPE上的重要接触残留物是 活动所需；b)SPE C的特征，可能还有SPE J的特征 穿透粘膜表面的能力。研究将包括建立 阴道上皮单层和复层上皮 毒素(S)穿透蛋鸡的机制的评估。我们会 也要评估生物非活性毒素渗透 上皮细胞，在体外和在兔体内，作用于其他试剂，从而确定 类毒素是否可用作递送剂(以及可能的佐剂) 用于经粘膜免疫；以及c)表征 兔链球菌中毒性休克综合征合并坏死性筋膜炎。我们 假设SPE通过以下途径引起低血压和吞噬延迟 夸大的细胞因子释放，这反过来又允许细胞继续增长 通过溶血素产生坏死性筋膜炎的侵袭性生物 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.