MOLECULAR INTERACTIONS BETWEEN SPEA AND THE TCR

描述(改编自申请人的摘要)：近年来 无论是国内还是国外，都出现了严重的、经常的 化脓性链球菌致生命危险感染(A组 链球菌)。许多患者的症状都与此相关 葡萄球菌中毒性休克综合征，并将其命名为链球菌 中毒性休克综合征(STSS)被归因于这些侵入性疾病 链球菌感染。有强有力的流行病学证据 链球菌热原外毒素A(SPEA)在猪瘟发病机制中的作用 STSS。SPEA是一种细菌超抗原，它能够与 II类主要组织相容性分子，激活一大部分 T细胞的数量。STSS等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 来自活化的T细胞的生物活性细胞因子。 SPEA和其他细菌(和病毒)蛋白被称为超抗原 由于它们与第二类MHC相互作用的独特机制 表达抗原提呈细胞和T淋巴细胞。超抗原 与II类MHC作为完整分子结合在不同于 抗原提呈沟。除了结合II类MHC 分子、超抗原与T细胞受体(TCR)在某些区域相互作用 由V基因片段编码。每个超抗原激活一组特定的 V-β链编码的T细胞，因此能够激活更大的 T细胞群体的百分比高于传统的多肽抗原。 这项拨款提案的目标是详细研究 SPEA和人类TCR之间的关系。SPEA所需的氨基酸残基 将定义富有成效的TCR交互。V-β链氨基酸 将确定与SPEA进行有效相互作用所需的残留物。 这些研究将包括测量毒素的亲和力- V-Beta交互作用。此外，毒素的X射线晶体结构， 突变的和等位的毒素形式，以及与人类完成的毒素 将确定V-β链。 这些数据将有助于描述激活 被超抗原激活的T细胞。此外，这里获得的数据是 设计和开发化合物的第一步，如TCR特定 多肽，以干扰SPEA-TCR的相互作用，进而阻止 SPEA不能作为超抗原。可能会有这样的组件 具体地说，阻断SPEA的超抗原能力可能证明 作为改善和可能预防感染的STSS的有效治疗方法 个人的。

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.