Activity of Pseudomonas Type III Toxins

了解寄主和寄生虫之间的动态相互作用提供了防止损害 寄主组织，并限制寄生复制。假单胞菌III型系统在急性呼吸窘迫综合征中起重要作用 感染，并可能在慢性感染的建立中起到初始作用。四种效应器或毒素， ExOS、ExoT、ExoY和ExoU通过分泌器直接注射到真核细胞中 共享重要的属性。每个效应器是一个酶，每个酶都需要一个真核辅因子或 最大活性的激活剂。催化活性确保快速中毒和细胞生理变化 以利于细菌在宿主环境中的复制和生存。细胞内关键成分的失活 包括对吞噬和细菌破坏很重要的细胞骨架成分的防御(EXOS， ExoT、ExoY)、细胞间相互作用(ExoY)、细胞信号通路(ExOS、ExoT、ExoY)和膜 完整性(ExoU)改变先天免疫反应，不仅有助于确定感染，而且还有助于 允许表达其他毒力因子，以促进传播到其他组织。当前应用程序 建立在我们对ExoU(磷脂酶)作用机制的发现和最新数据的基础上 超氧化物歧化酶(SOD)作为ExoU的辅因子。重要的是，哺乳动物的超氧化物歧化酶局限于这两种动物 细胞内和细胞外的隔间。我们假设ExoU-的辅因子的局部化。 磷脂酶活性可以控制酶的生物活性，并促进定植或 在细菌入侵的特定阶段传播。了解酶的关键元素是如何 共同作用改变蛋白质的活性将允许合理开发干扰 严重铜绿假单胞菌感染的病理后果。重要的是，这些研究可能揭示 关于辅因子、细菌酶和它们之间关系的进化见解 哺乳动物同源物(JPLA2、cPLA2和Patatin)。脂代谢与花生四烯酸的产生 酸影响免疫功能和细胞新陈代谢的调节。调查生物 ExoU中毒的后果可能导致对P。 铜绿假单胞菌及其产品，并可能导致设计一种治疗方法的组合，可以帮助 危重或处于慢性感染早期阶段的个人。

Understanding the dynamic interaction between host and parasite offers opportunities to prevent damage to host tissues and limit parasitic replication. The Pseudomonas type III system plays an important role in acute infections and may play an initial role in the establishment of chronic infections. Four effectors or toxins, ExoS, ExoT, ExoY and ExoU, are directly injected into eukaryotic cells by the secretion apparatus and all share important properties. Each effector is an enzyme and each enzyme requires a eukaryotic cofactor or activator for maximal activity. Catalytic activity ensures rapid intoxication and alteration of cellular physiology to benefit bacterial replication and survival in a host environment. Inactivation of key elements of cellular defenses that include cytoskeletal components important for phagocytosis and bacterial destruction (ExoS, ExoT, ExoY), intercellular interactions (ExoY), cell signaling pathways (ExoS, ExoT, ExoY) and membrane integrity (ExoU) alter the innate immune responses and can aid not only in establishing the infection but also allow expression of other virulence factors to promote dissemination to other tissues. The current application builds upon our discovery of the mechanism of action of ExoU (phospholipase) and recent data implicating superoxide dismutase (SOD) as a cofactor for ExoU. Importantly, mammalian SODs are localized to both intracellular and extracellular compartments. We postulate that the localization of the cofactor for ExoU- phospholipase activity may govern the biologic activities of the enzyme and promote either colonization or dissemination at certain stages of bacterial invasion. Understanding how the elements critical to enzymatic activity work together to alter the protein will allow rational development of inhibitors that interrupt the pathological consequences of serious P. aeruginosa infections. Importantly, these studies could reveal evolutionary insights regarding the relationships between the cofactors, bacterial enzymes and their mammalian homologs (JPLA2, cPLA2 and patatin). Finally lipid metabolism and the production of arachidonic acids effect immune function and the regulation of cellular metabolism. Investigating the biological consequences of ExoU intoxication may lead to new insights regarding the inflammatory response to P. aeruginosa and its products and may result in the design of a combination of therapeutics that could aid individuals who are critically ill or in the early stages of chronic infection.