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Mechanisms and Treatment of Chronic, Latent Human Strongyloidiasis

慢性、潜伏性人类类圆线虫病的机制和治疗

基本信息

批准号：
9232990
负责人：
DAVID ABRAHAM
金额：
$ 46.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232990
关键词：
Acids Adrenal Cortex Hormones Affect Agonist Alpha Cell Animal Model Bile Acids Biological Assay Blindness Caenorhabditis elegans Canis familiaris Cells Child Chronic Clinical Communities Data Development Diagnosis Diarrhea Disease Dose Drug Targeting Drug effect disorder Effector Cell Environment Event Experimental Models Failure to Thrive Female Generations Gerbils HTLV-1 Infection Hormones Human Human T-lymphotropic virus 1 Immune Immune response Immune system Immunocompromised Host Immunosuppression Immunosuppressive Agents In Vitro Individual Infection Intestines Larva Lead Life Ligands Modeling Mus Nematoda Nematode infections Nuclear Hormone Receptors Parasites Parasitic nematode Patient risk Patients Pharmaceutical Preparations Phase Population Process Receptor Signaling Regulation Reporter Residual state Resistance Role Signal Pathway Signal Transduction Soil Steroid therapy Steroids Strongyloides stercoralis Strongyloidiasis Syndrome System Testing Virulent base chemotherapy efficacy testing enteritis eosinophil experimental study high throughput screening immune function in vivo in vivo Model latent infection macrophage mouse model multidisciplinary neutrophil permissiveness prednisolone prevent receptor senescence small molecule libraries success synthetic enzyme

项目摘要

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.

项目摘要肠道寄生线虫粪类圆线虫（Strongyloides stercoralis）感染约1亿人全球范围内，美国贫困社区估计有100，000人。在其简单的形式，人类类圆线虫病导致儿童慢性肠炎、腹泻和发育不良，常见于其他土壤传播的线虫感染。与其他寄生线虫不同，S.斯特克罗利斯群岛能够自我感染，因此在个体宿主中自我复制。自身感染可能发生在低，它的水平得到很好的调节，并引起慢性、潜伏感染，这种感染显然可以持续宿主的一生。在接受免疫抑制性化疗或感染HTLV-1的患者中，这些异常慢性感染可能进展到自身感染失调的状态，导致潜在的致命性播散性过度感染使用甾体类免疫抑制剂经常与发作相关高感染性类圆线虫病，并能刺激自身感染。动物模型中的粪杆菌。在其在探索阶段，该项目将研究类固醇调节S. 粪虫我们将测试三个不相互排斥的假设，这种调节是如何发生的。第一有两种假说是相关的，认为药用类固醇或其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下进行检验，常见的药用类固醇如泼尼松龙或其常见代谢物可激活Ss-beta-12 在基于细胞的报告基因测定中的信号传导。体内实验将确定是否预处理幼虫S。当这些寄生虫被接种到一个主持人类固醇调节自身感染的第三个假设是，这是以间接的方式发生的，通过抑制宿主的免疫系统，从而使其更加宽容， for this process过程.我们将在R21期的目标2下通过消融免疫效应细胞来检验这一假设。保留在先天性免疫缺陷NSG小鼠中的群体，并确定是否自身感染的发生与类固醇治疗无关。里程碑的实现，包括对S. Stercoralis将支持项目进展到R33转化阶段其中，在Aim-3下，作为来自用于高通量筛选的现有系统的命中产生的化合物， Ss-STAT-12激动剂和拮抗剂的小分子文库将优先用于体内测试。根据R33阶段的目标4，将在沙鼠模型中测试命中物预防自身感染的功效模拟药物诱导的自身感染，如果R21期的结果允许，在NSG小鼠模型中，由潜在免疫缺陷刺激的自发性自身感染。表示成功的里程碑 R33相将是清除超慢性S三种先导化合物。粪感染