Pathogenesis of Life Threatening Box Jellyfish Envenomation and Irukandji Syndrome

箱形水母毒液蛰伤造成了无数临床上显著的后遗症，包括使人衰弱的螫刺部位 疼痛和Irukandji综合征，以及罕见的急性心血管衰竭和死亡， 居民和游客到美国沿海地区的夏威夷，关岛，塞班岛，佛罗里达，美属维尔京群岛和 波多黎各。在热带和亚热带地区，立方虫叮咬也是一种日益严重的公共卫生威胁。 澳大利亚、印度尼西亚、泰国、加勒比海盆地、地中海和印度洋。因此， 迫切需要更好地了解Irukandji综合征的发病机制，这是一种可能危及生命的疾病， 多系统症状和体征的后遗症，提示“细胞因子风暴”和“儿茶酚胺激增”。 我们的长期目标是为所有的立方动物开发快速诊断和有效的治疗方法 毒液对于所提议的研究，我们的主要目标是阐明毒液孔蛋白在 Irukandji综合征的发病机制，通过采用先前建立的体外和体内模型系统。 我们的中心假设是立方动物的孔形成蛋白，或孔蛋白，诱导多米诺骨牌式的级联反应， 对血小板、红细胞和外周血单核细胞的时间依赖性病理生理学影响， 包括生物胺和储存的细胞因子的初始剂量依赖性释放，这反过来又导致 次级诱导幼稚白细胞以及内皮细胞释放细胞因子，包括 Irukandji综合征。毒液生物化学家和动物模型专家将实现以下具体目标。 目标1.比较了立方动物全毒和纯化孔蛋白对体外细胞增殖的剂量和时间依赖性影响。 人外周血单核细胞和血小板。 目标2.比较立方动物全毒和纯化孔蛋白在仔猪体内的剂量依赖效应。 将使用基于全血细胞的测定和仔猪动物模型来确定立方动物孔蛋白是否 引起特定的全身炎症效应并追踪连续的生理和生化反应 在时间进程实验中。初步研究表明，生命发病机制的一个核心方面- 威胁性水母毒液蛰入和Irukandji综合征涉及免疫细胞对立方动物的反应 毒液因此，这个探索性的研究项目解决了一个关键的未满足的需要，以更好地了解 研究立方动物孔蛋白的病理生理作用，以开发快速诊断和有效治疗方法。

Box jellyfish envenomations account for myriad clinically significant sequelae, including debilitating sting-site pain and Irukandji syndrome, as well as in rare instances acute cardiovascular collapse and death, among residents and visitors to the U.S. coastal areas of Hawaii, Guam, Saipan, Florida, U.S. Virgin Islands and Puerto Rico. Cubozoan stings are also an increasing public health threat worldwide in tropical and subtropical areas of Australia, Indonesia, Thailand, Caribbean basin, Mediterranean Sea and Indian Ocean. Thus, there is an urgent need to better understand the pathogenesis of Irukandji syndrome, a potentially life-threatening sequelae with multi-systems symptoms and signs, suggestive of “cytokine storm” and “catecholamine surge”. Our long-term goal is to develop rapid diagnostics and effective treatments for the full spectrum of cubozoan envenomations. For the proposed research, our primary objective is to clarify the role of venom porins in the pathogenesis of Irukandji syndrome, by employing previously established in vitro and in vivo model systems. Our central hypothesis is that the cubozoan pore-forming proteins, or porins, induce a domino-type cascade of time-dependent pathophysiological effects on platelets, erythrocytes and peripheral blood mononuclear cells, including an initial dose-dependent release of biogenic amines and stored cytokines, which in turn causes a secondary induction of cytokine release from naïve leucocytes, as well as endothelial cells, that comprises Irukandji syndrome. A venom biochemist and an animal model expert will achieve the following specific aims. Aim 1. Compare the in vitro dose- and time-dependent effects of cubozoan whole venom and purified porin on human peripheral blood monocytes and platelets. Aim 2. Compare the in vivo dose-dependent effects of cubozoan whole venom and purified porin in piglets. Whole blood cell-based assays and a piglet animal model will be used to determine whether cubozoan porins cause specific systemic inflammatory effects and to track sequential physiological and biochemical responses in time-course experiments. Preliminary studies demonstrate that a central aspect of the pathogenesis of life- threatening jellyfish envenomation and Irukandji syndrome involves immune cell responses to cubozoan venom. Thus, this exploratory research project addresses a critical unmet need to better understand the pathophysiological role of cubozoan porin in order to develop rapid diagnostics and effective treatments.