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: 8508358
• 负责人: DAVID ABRAHAM
• 金额: $ 21.67万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508358
• 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; Ligands; Modeling; Mus; Nematoda; Nematode infections; Nuclear Hormone Receptors; Parasites; Parasitic nematode; Patients; Pharmaceutical Preparations; Phase; Population; Process; Receptor Signaling; Regulation; Reporter; Residual state; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Simulate; 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; public health relevance; receptor; research study; senescence; small molecule libraries; success; synthetic enzyme

DESCRIPTION (provided by applicant): 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 lfe 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.

描述（由申请方提供）：肠道寄生线虫粪类圆线虫感染全球约1亿人，估计美国贫困社区有10万人感染。在其简单的形式，人类类圆线虫病导致慢性肠炎，腹泻和未能茁壮成长的儿童，一个共同的综合征，其他土壤传播的线虫感染。与其他寄生线虫不同，S.粪绦虫能够自身感染，因此能够在个体宿主中自我复制。自身感染可能发生在一个较低的良好调节的水平，并引起慢性，潜伏感染，显然可以持续宿主的生命。在接受免疫抑制化疗或感染HTLV-1的患者中，这些极慢性感染可能进展到自身感染失调的状态，导致潜在致命的播散性过度感染。类固醇免疫抑制剂的使用经常与高感染性类圆线虫病的发作有关，并可刺激自身感染。动物模型中的粪杆菌。在其探索阶段，本项目将研究类固醇调节自身感染的机制。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。前两种假说是相关的，并认为药用类固醇或其宿主代谢产物，分别直接作用于寄生虫通过其SS-12核激素受体刺激和维持自身感染。这两个假设将在该项目R21阶段的目标1下进行测试，方法是确定常见的药用类固醇（如泼尼松龙或其常见代谢物）是否可以在基于细胞的报告基因测定中激活Ss-STAT-12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宿主中时，具有药用类固醇的粪寄生虫可以增强自身感染。类固醇调节自身感染的第三个假设是，这是通过抑制宿主的免疫系统以间接的方式发生的，从而使其对这一过程更加宽容。我们将在R21阶段的目标2下通过消融保留在先天性免疫缺陷NSG小鼠中的免疫效应细胞群并确定自身感染是否独立于类固醇治疗而发生来检验这一假设。达到里程碑，包括类固醇对S的直接作用的证据。Stercoralis将支持该项目进展到翻译R33阶段，在该阶段，根据目标3，从用于高通量筛选小分子文库的Ss-STAT-12激动剂和拮抗剂的现有系统中产生的化合物将优先用于体内测试。在R33阶段的目标4下，将在模拟药物诱导的自身感染的沙鼠模型中，以及如果R21阶段的结果允许，在由潜在免疫缺陷刺激的自发性自身感染的NSG小鼠模型中，检测命中预防自身感染的有效性。表明R33阶段成功的关键是三种清除超慢性S的先导化合物。粪感染