Role of schistosome ABC transporters in modulation of host immune responses

描述（由申请人提供）：血吸虫病是一种毁灭性的、潜在致命的热带疾病，影响着全世界数亿人。在缺乏治疗的情况下，血吸虫感染是慢性和持续性的，通常持续数年或数十年，对各种器官造成严重和永久性的损害，严重发病率，在某些情况下甚至死亡。这种疾病是由血吸虫属的寄生扁虫引起的。虽然血吸虫不会在宿主体内复制，但它们每天会产生成百上千的卵。那些没有排出体外的卵子留在宿主体内，引起免疫病理反应，从而导致慢性疾病。宿主免疫系统对血吸虫感染的反应在很大程度上决定了保护性免疫（健康）和免疫病理（发病率）之间的平衡。一些研究表明，从卵和蠕虫中排泄、分泌或衍生的分子具有强大的免疫调节特性，但这些因子呈现给宿主的潜在机制仍然难以捉摸。其中一些分子是ATP结合盒（ABC）蛋白的潜在底物。ABC超家族蛋白的成员是与多药耐药现象相关的外排转运蛋白。除了在药物和毒素的外排中发挥作用外，ABC转运蛋白还在包括免疫功能调节在内的多种生理过程中发挥关键作用。例如，它们以高亲和力运输已知的免疫调节剂，参与抗原呈递，并参与免疫功能的调节，如T细胞迁移、T辅助细胞极化和树突状细胞成熟和迁移。我们假设血吸虫使用其ABC转运蛋白的一个子集来介导形成宿主免疫反应和影响病理的寄生虫信号分子的排泄、分泌或呈现。该项目的具体目标将集中在寄生虫卵引起的宿主反应上，在体外（目的1）和体内（目的2）验证这一假设。这些实验将提供一个独特的机会来定义宿主t细胞反应极化的基本分子机制。我们得到的初步结果支持了我们的假设，并说明了所提出的实验的可行性。这个探索性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，也有望提供新的治疗靶点，可以用来减少或消除疾病病理。

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.