Role of schistosome ABC transporters in modulation of host immune responses

血吸虫ABC转运蛋白在调节宿主免疫反应中的作用

• 批准号: 8530700
• 负责人: ROBERT M GREENBERG
• 金额: $ 24万
• 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/8530700
• 关键词: ATP-Binding Cassette Transporters; Address; Affect; Affinity; Antigen Presentation; Antigens; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Maturation; Cell membrane; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Dendritic Cells; Dendritic cell activation; Disease; Drug Efflux; Equilibrium; Excision; Excretory function; Female; Genetic; Health; Helminths; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immune system; Immunity; Immunomodulators; In Vitro; Infection; Inflammatory; Intervention; Lead; Life Cycle Stages; Lipopolysaccharides; Measures; Mediating; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Organ; Parasites; Pathology; Physiological Processes; Platyhelminths; Play; Production; Property; Proteins; RNA Interference; Regulation; Role; Schistosoma; Schistosoma japonicum; Schistosoma mansoni; Schistosomiasis; Severities; Shapes; Signaling Molecule; Staging; T cell response; T-Lymphocyte; Testing; Toll-Like Receptor Pathway; Toxin; Tropical Disease; Xenobiotics; base; cell motility; cytokine; design; egg; immune function; immunopathology; immunoregulation; in vivo; in vivo Model; inhibitor/antagonist; insight; member; neglect; new therapeutic target; protein transport; public health relevance; pulmonary granuloma; research study; response

DESCRIPTION (provided by applicant): Schistosomiasis is a devastating, potentially fatal tropical disease that affects hundreds of millions worldwide. In the absence of treatment, schistosome infections are chronic and persistent, often lasting for years or decades, resulting in significant and permanent damage to various organs, severe morbidity, and, in some cases, death. The disease is caused by parasitic flatworms of the genus Schistosoma. Though schistosomes do not replicate within the host, they produce hundreds or thousands of eggs each day. Those eggs that are not excreted remain within the host and evoke an immunopathological response that can lead to chronic disease. How the host immune system responds to schistosome infection determines in large part the balance between protective immunity (health) and immunopathology (morbidity). Several studies have shown that molecules excreted, secreted, or derived from both eggs and worms have potent immunomodulatory properties, but the underlying mechanisms by which these factors are presented to the host have remained elusive. Some of these molecules are potential substrates of ATP binding cassette (ABC) proteins. Members of the ABC superfamily of proteins are efflux transporters associated with the phenomenon of multidrug resistance. In addition to their roles in efflux of drugs and toxins, ABC transporters play critical roles in a wide variety of physiological processes including regulation of immune function. For example, they transport known immunomodulators with high affinity, are involved in antigen presentation, and have been implicated in modulation of immune functions such as T cell migration, T helper cell polarization, and dendritic cell maturation and migration. We hypothesize that schistosomes use a subset of their ABC transporters to mediate excretion, secretion, or presentation of parasite signaling molecules that shape host immune responses and influence pathology. The specific aims of this project will focus on parasite egg-evoked host responses, testing this hypothesis both in vitro (Aim 1) and in vivo (Aim 2). These experiments will provide a unique opportunity to define basic molecular mechanisms underlying polarization of host T-cell responses. Preliminary results we have obtained support our hypothesis, and speak to the feasibility of the proposed experiments. This exploratory project provides a unique opportunity to define basic molecular mechanisms underlying parasite-host interactions, and also holds the promise of offering new therapeutic targets that can be exploited to reduce or eliminate disease pathology.

描述（由申请人提供）：血吸虫病是一种毁灭性的，可能致命的热带疾病，影响全球数亿人。在没有治疗的情况下，寄生虫感染是慢性和持续性的，通常持续数年或数十年，导致对各种器官的重大和永久性损伤，严重发病率，以及在某些情况下死亡。这种疾病是由血吸虫属的寄生扁虫引起的。虽然寄生虫体不会在宿主体内复制，但它们每天会产生数百或数千个卵。那些没有被排出的卵留在宿主体内，引起免疫病理反应，可能导致慢性疾病。宿主免疫系统对血吸虫感染的反应方式在很大程度上决定了保护性免疫（健康）和免疫病理学（发病率）之间的平衡。一些研究表明，从卵和蠕虫分泌、分泌或衍生的分子具有有效的免疫调节特性，但这些因子呈递给宿主的潜在机制仍然难以捉摸。这些分子中的一些是ATP结合盒（ABC）蛋白的潜在底物。ABC蛋白超家族的成员是与多药耐药现象相关的外排转运蛋白。除了它们在药物和毒素外排中的作用之外，ABC转运蛋白在包括免疫功能调节在内的各种生理过程中发挥关键作用。例如，它们以高亲和力转运已知的免疫调节剂，参与抗原呈递，并且涉及免疫功能的调节，例如T细胞迁移、T辅助细胞极化和树突细胞成熟和迁移。我们假设，寄生虫体使用其ABC转运蛋白的一个子集来介导排泄、分泌或呈递寄生虫信号分子，这些寄生虫信号分子塑造宿主免疫反应并影响病理。本项目的具体目标将集中在寄生虫卵诱发的宿主反应，测试这一假设在体外（目标1）和体内（目标2）。这些实验将提供一个独特的机会，以确定基本的分子机制，宿主T细胞反应的极化。 我们已经获得的初步结果支持我们的假设，并发言的可行性所提出的实验。这个探索性的项目提供了一个独特的机会来定义寄生虫-宿主相互作用的基本分子机制，并且还有望提供可用于减少或消除疾病病理的新的治疗靶点。