CARDIOTOXICITY OF STREPTOCOCCAL PYROGENIC EXOTOXIN

本研究对A群链球菌感染的发病机制(S)进行了研究。 热源性外毒素(SPE)使宿主容易受到心肌损伤和 其他毒剂的致命电击，也许是这些中最重要的特性 毒素。将尝试确定毒素上的位置(表位) 结合抗体，包括中和，免疫系统细胞和 心脏细胞，试图确定生物所需的区域 毒性。SPE有能力引起猩红热，一种中毒性休克 综合征样疾病，并可能导致早期事件在 风湿热、其他自身免疫性疾病和血管疾病的发展 晚年的疾病。研究阐明了增强的机制 对心肌损伤和休克的易感性将在几个 方向。将对具有代表性的外毒素A型和C型进行检测 与心脏和肝脏细胞特异结合的能力，以及 脾细胞。分离的心脏和肝脏细胞将被研究为 最有可能被强化的目标。单独的外毒素，结合在一起， 并将与内毒素(一种具有代表性的第二种制剂)一起进行测试 对于破坏细胞膜完整性的能力，改变大分子 合成，诱导白细胞介素1，改变内毒素摄取和随后 解毒。研究确定靶细胞相互作用的位置和 抗体结合将从三个方向进行。单克隆抗体 针对SPE，A和C将被用来阻止生物活性。 蛋白水解酶、其他裂解剂和基因技术将 用于产生具有部分生物活性的毒素片段， 结合细胞和抗体的能力。

The research studies the mechanism(s) by which group A streptococcal pyrogenic exotoxins (SPES) predispose the host to myocardial damage and lethal shock by other agents, perhaps the most important property of these toxins. Attempts will be made to identify sites (epitopes) on the toxins which bind antibodies, including neutralizing, immune system cells and heart cells, in attempts to identify regions necessary for biological toxicity. The SPEs have the capacity to cause scarlet fever, a toxic-shock syndrome-like illness, and may contribute to the early events in development of rheumatic fever, other autoimmune diseases, and vascular diseases later in life. Research to elucidate the mechanism of enhanced susceptibility to myocardial damage and shock will proceed in several directions. SPE types A and C, as representative exotoxins, will be tested for capacity to bind specifically to heart and liver cells, and splenocytes. Isolated heart and liver cells will then be investigated as the most likely targets for enhancement. Exotoxins alone, in combination, and together with endotoxin (a representative second agent) will be tested for capacity to disrupt cell membrane integrity, alter macromolecular synthesis, induce interleukin 1, and alter endotoxin uptake and subsequent detoxification. Studies to identify sites for target cell interaction and antibody binding will proceed in three directions. Monoclonal antibodies against SPEs A and C will be used to block biological activities. Proteolytic enzymes, other cleavage agents, and genetic techniques will be used to generate toxin fragments with partial biological activities, capacities to bind cells and antibodies.