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

• 批准号: 9008341
• 负责人: JAMES B LOK
• 金额: $ 47.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008341
• 关键词: Acids; Adrenal Cortex Hormones; Affect; Agonist; Animal Model; Bile Acids; Biological Assay; Blindness; Caenorhabditis elegans; Canis familiaris; Cells; Child; Chronic; Communities; Data; Development; Diagnosis; Diarrhea; Disease; Dose; Drug Targeting; Drug effect disorder; Effector Cell; Environment; Event; Failure to Thrive; Female; Generations; Gerbils; Hormones; Human; Human T-lymphotropic virus 1; Immune; Immune response; Immune system; Immunocompromised Host; Immunosuppressive Agents; In Vitro; Individual; Infection; Intestines; Larva; Lead; Left; 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; high throughput screening; immune function; in vivo; in vivo Model; latent infection; macrophage; mouse model; multidisciplinary; neutrophil; prednisolone; prevent; receptor; research study; senescence; small molecule libraries; success; synthetic enzyme

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.

项目概要 肠道寄生线虫粪类圆线虫感染约 1 亿人 全球范围内约有 100,000 人生活在美国的贫困社区。以不复杂的形式， 人类类圆线虫病会导致慢性肠炎、腹泻和儿童生长迟缓，这是一种综合征 常见于其他土壤传播的线虫感染。与其他寄生线虫不同，粪圆线虫 能够自我感染，因此能够在个体宿主中自我复制。自身感染可能发生在低、 水平得到良好调节，并引起慢性、潜伏感染，这种感染显然可以持续宿主的一生。 在接受免疫抑制化疗或感染 HTLV-1 的患者中，这些 慢性感染可能会发展到自身感染失调的状态，从而导致潜在的致命 播散性过度感染。类固醇免疫抑制剂的使用经常与发作相关 过度感染性类圆线虫病，并且可以在动物模型中刺激粪圆线虫的自身感染。在其 在探索阶段，该项目将研究类固醇调节金黄色葡萄球菌自身感染的机制。 粪类圆线虫。我们将测试关于这种调节如何发生的三个非互斥假设。第一个 两个相关的假设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，以确定是否 常见的药用类固醇如泼尼松龙或其常见代谢物可以激活Ss-DAF-12 基于细胞的报告基因检测中的信号传导。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体内时，带有药用类固醇的粪类圆线虫会增强自身感染。 主持人。类固醇调节自身感染的第三个假设是，这种情况以间接方式发生 通过抑制宿主的免疫系统来尊重寄生虫，从而使其更加宽容 对于这个过程。我们将通过消除免疫效应细胞在 R21 阶段的目标 2 下测试这一假设 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，包括以下证据： 对粪圆线虫的直接类固醇作用将支持该项目进展至转化 R33 阶段 其中，在 Aim-3 下，化合物作为来自现有高通量筛选系统的命中而产生 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，并且，如果 R21 相的结果允许，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。表明成功的里程碑 R33阶段将是清除超慢性粪圆线虫感染的三种先导化合物。