MOLECULAR INTERACTIONS BETWEEN SPEA AND THE TCR

描述（改编自申请人摘要）：近年来， 在这个国家和国外， 化脓性链球菌（A组）引起的危及生命的感染 streaming）。 许多患者的症状与此相关 葡萄球菌中毒性休克综合征， 中毒性休克综合征（STSS）已被分配给这些侵入性 链球菌感染 有强有力的流行病学证据 提示链球菌致热性外毒素A（SpeA）在 STSS。 SpeA是一种细菌超抗原，与 II类主要组织相容性分子，激活大部分 的T细胞。 STSS和其他细菌超抗原介导的病理学研究 疾病被认为是由于大量和不受管制的释放， 从活化的T细胞中提取生物活性细胞因子。 SpeA和其他细菌（和病毒）蛋白被称为超抗原 由于它们与II类MHC相互作用的独特机制， 表达抗原呈递细胞和T淋巴细胞。 超抗原 与II类MHC结合，作为完整分子，在不同于 抗原呈递沟 除了结合II类MHC 分子，超抗原与T细胞受体（TCR）相互作用的区域 由V基因片段编码 每一种超抗原激活一组特定的 V-β链编码T细胞，因此能够激活一个更大的 T细胞群的百分比。 这项拨款提案的目标是详细研究 SpeA和人类TCR之间的联系 SpeA的氨基酸残基需要 将定义有效的TCR相互作用。 V-β链氨基酸 将鉴定与SpeA有效相互作用所需的残基。 这些研究将包括测量毒素的亲和力- V-beta相互作用 另外，毒素的X射线晶体结构， 突变体和等位基因毒素形式，以及与人一起完成的毒素 将测定V-β链。 这些数据将有助于表征激活一个细胞所需的相互作用。 T细胞的超抗原。 此外，这里获得的数据是 设计和开发化合物的第一步，例如TCR特异性 肽，以干扰SpeA-TCR相互作用，并反过来阻止 SpeA作为超抗原。 可能的是， 特异性阻断SpeA的超抗原能力可能证明 可用作改善并可能预防感染者STSS的治疗方法 单独的.

DESCRIPTION (Adapted from the applicant's abstract): In recent years in both this country and abroad, there has been a resurgence of acute, often life threatening infections due to Streptococcus pyogenes (group A streptococcus). Many patients experience symptoms mimicking this associated with staphylococcal toxic shock syndrome, and the designation streptococcal toxic shock syndrome (STSS) has been assigned to these invasive streptococcal infections. There is strong epidemiologic evidence implicating streptococcal pyrogenic exotoxin A (SpeA) in the pathogenesis of STSS. SpeA is a bacterial superantigen that is capable, in combination with class II major histocompatibility molecules, of activating a large fraction of T cells. The pathology of STSS and other bacterial superantigen mediated disease is believed to result from the massive and unregulated release of bioactive cytokines from the activated T cells. SpeA and other bacterial (and viral) proteins have been termed superantigens due to their unique mechanisms of interacting with the class II MHC expressing antigen-presenting cells and the T lymphocytes. Superantigens bind to class II MHC as intact molecules at sites distinct from the antigen-presenting groove. In addition to binding the class II MHC molecule, superantigens interact with the T cell receptor (TCR) in regions encoded by the V-gene segments. Each superantigen activates a specific set of V-beta chain-encoding T cell, and thus is able to activate a much larger percentage of the T cell population than conventional peptide antigens. The goals of this grant proposal are to examine in detail the interaction between SpeA and the human TCR. The amino acid residues of SpeA needed for a productive TCR interaction will be defined. V-beta chains amino acids residues needed for a productive interaction with SpeA will be identified. These studies will include measurements of the affinities of the toxin- V-beta interactions. In addition, the X ray crystal structure of the toxin, mutant and allelic toxin forms, as well as the toxin completed with a human V-beta chain will be determined. These data will help characterize the interaction needed for activation of a T cell by the superantigen. In addition, the data obtained here are the first step in the design and development of compounds, such as TCR specific peptides, to interfere with the SpeA-TCR interaction, and in turn prevent SpeA from acting as a superantigen. It is possible that components that can specifically block the superantigenic capabilities of SpeA might prove useful as treatments to ameliorate and possibly prevent STSS in an infected individual.