MOLECULAR INTERACTIONS BETWEEN SPEA AND THE TCR

描述（改编自申请人的摘要）：近年来 无论是在国内还是在国外，严重的、经常 化脓性链球菌（A 组）引起的危及生命的感染 链球菌）。 许多患者会出现与此相关的症状 患有葡萄球菌中毒性休克综合征，并且被称为链球菌 中毒性休克综合症（STSS）已被归入这些侵入性的 链球菌感染。 有强有力的流行病学证据 链球菌热原性外毒素 A (SpeA) 与以下疾病的发病机制有关 STSS。 SpeA 是一种细菌超抗原，能够与 II 类主要组织相容性分子，可激活大部分 T 细胞。 STSS 和其他细菌超抗原介导的病理学 据信，疾病是由大量且不受管制的释放造成的 来自激活的 T 细胞的生物活性细胞因子。 SpeA 和其他细菌（和病毒）蛋白被称为超级抗原 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 在与 II 类 MHC 不同的位点上作为完整分子结合 抗原呈递沟。 除了结合 II 类 MHC 分子，超级抗原与区域中的 T 细胞受体 (TCR) 相互作用 由V基因片段编码。 每个超级抗原都会激活一组特定的超级抗原 V-β链编码T细胞，因此能够激活更大的 T 细胞群比传统肽抗原的百分比。 该拨款提案的目标是详细检查相互作用 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 相互作用。 V-β链氨基酸 将鉴定与 SpeA 产生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-β 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，以及用人类完成的毒素 V-β链将被确定。 这些数据将有助于表征激活所需的交互 T细胞由超抗原产生。 另外，这里获得的数据是 化合物设计和开发的第一步，例如 TCR 特异性 肽，干扰 SpeA-TCR 相互作用，进而阻止 SpeA 充当超抗原。 组件可能可以 特异性阻断 SpeA 的超抗原能力可能会证明 可用作改善和可能预防感染者 STSS 的治疗方法 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.