Mechanisms and Treatment of Chronic, Latent Human Strongyloidiasis

项目总结 肠道寄生线虫粪类圆线虫感染约1亿人 在全球范围内，估计有10万人生活在美国的贫困社区。以其简单的形式， 人类弓形虫病会导致慢性肠炎、腹泻和儿童发育不良，这是一种综合征 在其他土传线虫感染中很常见。与其他寄生线虫不同的是，S。 能够自我感染，从而在单个宿主中自我复制。自体感染可能发生在低水平， 这种病毒的水平受到很好的调控，并会引起慢性潜伏性感染，显然可以持续宿主的一生。 在接受免疫抑制化疗或感染HTLV-1的患者中，这些 慢性感染可能会发展到自我感染失控的状态，导致潜在的致命 播散性过度感染。使用类固醇免疫抑制剂经常与癫痫发作有关。 在动物模型中可引起严重感染性的管圆线虫病，并可引起管圆线虫的自身感染。在ITS中 在探索阶段，该项目将研究类固醇调节自体感染的机制。 菊科植物。我们将测试关于这一监管如何发生的三个非互斥假设。第一 两个假说是相关的，认为药物类固醇或它们的宿主代谢物分别起作用 通过其SS-DAF-12核激素受体直接作用于寄生虫，以刺激和维持自身感染。 这两个假设将在项目R21阶段的目标1下进行测试，以确定 常用药物类固醇如强的松龙或其常见代谢物可激活SS-DAF-12 以细胞为基础的报告分析中的信号。体内实验将确定是否对幼虫进行预处理。 当这些寄生虫被接种到含有药物类固醇的植物体内时，这些寄生虫可以加强自身感染 主持人。类固醇调节自身感染的第三个假说是，这是以间接的方式发生的 通过抑制宿主的免疫系统来尊重寄生虫，从而使其更具容许性 在这个过程中。我们将在R21阶段的目标2中通过消融免疫效应细胞来测试这一假设 保留在先天免疫缺陷NSG小鼠中的种群并确定 自身感染的发生与类固醇治疗无关。达到里程碑，包括以下证据 类固醇对斯特氏链球菌的直接作用将支持该项目进入翻译R33阶段。 其中，根据AIM-3，从用于高通量筛选的现有系统中产生的化合物 SS-DAF-12激动剂和拮抗剂的小分子文库将优先用于体内测试。 在R33阶段的目标4下，将在沙土鼠模型中测试HITS在预防自身感染方面的有效性 模拟药物诱导的自身感染，如果R21阶段的结果允许，在NSG小鼠模型中 由潜在的免疫缺陷刺激的自发性自身感染。标志着成功的里程碑 R33阶段将是三种先导化合物，用于清除超慢性斯特拉菌感染。

PROJECT SUMMARY The intestinal parasitic nematode Strongyloides stercoralis infects approximately 100 million people worldwide and an estimated 100,000 in impoverished communities in the USA. In its uncomplicated form, human strongyloidiasis results in chronic enteritis, diarrhea and failure to thrive in children, a syndrome common to other soil-transmitted nematode infections. Unlike other parasitic nematodes, S. stercoralis is capable of autoinfection, and therefore self-replication in individual hosts. Autoinfection may occur at a low, well-regulated level and give rise to chronic, latent infections that can apparently last for the life of the host. In patients subjected to immunosuppressive chemotherapy or infected by HTLV-1, these exceedingly chronic infections may progress to states in which autoinfection is dysregulated, resulting in potentially fatal disseminated hyperinfection. Use of steroidal immunosuppressants is frequently associated with episodes of hyperinfective strongyloidiasis, and can stimulate autoinfection by S. stercoralis in animal models. In its exploratory phase, this project will examine the mechanism by which steroids regulate autoinfection by S. stercoralis. We will test three non-mutually exclusive hypotheses of how this regulation occurs. The first two hypotheses are related and hold that medicinal steroids or their host metabolites, respectively, act directly on the parasite via its Ss-DAF-12 nuclear hormone receptor to stimulate and maintain autoinfection. These two hypotheses will be tested under Aim 1 of the R21 phase of the project by ascertaining whether common medicinal steroids such as prednisolone or its common metabolites can activate Ss-DAF-12 signaling in a cell based reporter assay. In vivo experiments will ascertain whether pre-treatment of larval S. stercoralis with medicinal steroids can potentiate autoinfection when these parasites are inoculated into a host. The third hypothesis of steroid regulation of autoinfection is that this occurs in an indirect manner with respect to the parasite by suppressing the host's immune system and thereby rendering it more permissive for this process. We will test this hypothesis under Aim 2 of the R21 phase by ablating immune effector cell populations that remain in the congenitally immune-deficient NSG mouse and ascertaining whether autoinfection occurs independent of steroid treatment. Attainment of milestones comprising evidence of direct steroid effects on S. stercoralis will support progression of the project to a translational R33 phase where, under Aim-3, compounds arising as hits from an existing system for high-throughput screening of small-molecule libraries for agonists and antagonists of Ss-DAF-12 will be prioritized for in vivo testing. Under Aim 4 in the R33 phase, hits will be tested for efficacy in preventing autoinfection in a gerbil model simulating drug-induced autoinfection, and, if results from the R21 phase allow, in an NSG mouse model of spontaneous autoinfection stimulated by underlying immune deficiency. Milestones indicating success in the R33 phase will be three lead compounds that clear hyperchronic S. stercoralis infection.