Characterization of the determinants of snail-schistosome compatibility

血吸虫病是一种由血吸虫属寄生扁虫引起的疾病。全世界有超过2.6亿人遭受这种疾病的折磨，因该病而损失的伤残调整寿命年与疟疾不相上下。作为其生命周期的一部分，血吸虫必须在特定种类的蜗牛中进行幼虫发育。蜗牛是大约18,000种不同寄生虫中几乎每一种的中间宿主，而它们对寄生虫成功的重要性因以下事实而突显出来：兼容的蜗牛宿主的存在往往决定了吸虫疾病的地理分布，如血吸虫病。促进我们理解是什么使一种蜗牛与一种特定的寄生扁虫物种相容，而另一种蜗牛不相容，这是非常有意义的。引起人类肠道血吸虫病的曼氏血吸虫与其相容的蜗牛宿主之一光滑生物一起出现，作为研究钉螺与血吸虫相容的决定因素的模型。对这一模型的研究已经确定与光滑芽孢杆菌免疫反应相关的体液和细胞因子是感染结果的关键决定因素，与宿主和寄生虫的遗传学/表观遗传学、蛋白质组/转录调控和环境因素协同作用。*我们的研究集中在描述光滑芽孢杆菌免疫反应的细胞和体液成分在幼虫攻击曼氏杆菌攻击过程中的界面。蜗牛免疫细胞对寄生虫的包裹是消除感染的关键。因此，对蜗牛来说，维持足够的免疫细胞群是至关重要的，能够将这些细胞招募到寄生虫表面，并让这些细胞启动适当的免疫效应器来杀死寄生虫。我们过去的工作涉及到成功反应的每一个要素，通过表征蜗牛中的第一个细胞生长因子，并证明在该生长因子的刺激下发展出来的细胞更适合杀死曼氏血吸虫。现在，由于这项工作，我们对光肩星天牛体内发生的免疫过程有了更深入的了解。我们也有试剂和生物检测方法，使我们能够用机械透镜研究蜗牛的免疫过程。我们建议继续我们的工作，通过处理两个特定的目标来表征光滑杆菌对曼氏血吸虫挑战的免疫反应，这两个目标是我们已经确定的成功清除钉螺寄生虫的核心，并建立了我们过去由NSERC DG支持的工作：*1.表征光滑杆菌血细胞的发育过程，并建立特定血细胞亚群在细胞介导的抗血吸虫免疫反应中的作用。*2.研究血细胞产生的促进细胞介导的杀灭幼虫的循环体液免疫因子。

Schistosomiasis is a disease caused by parasitic flatworms of the genus Schistosoma. It afflicts over 260 million people worldwide, and the disability-adjusted life years lost to this disease rival that of malaria. As a part of their life cycle, schistosomes must undertake their larval development within a specific species of snail. Snails serve as the intermediate host for almost every one of the ~18,000 different species of parasite flatworm, and their importance to the success of the parasite is highlighted by the fact that the presence of a compatible snail host often defines the geographical distribution of trematode diseases like schistosomiasis. There is a great deal of interest in advancing our understanding of what makes one snail compatible with a particular parasitic flatworm species, and another incompatible. Schistosoma mansoni, which causes intestinal schistosomiasis in humans, has emerged along with one of its compatible snail host species, Biomphalaria glabrata, as a model for studying the determinants of snail-schistosome compatibility. Studies of this model have identified humoral and cellular factors associated with the B. glabrata immune response as key determinants of infection outcomes, acting in concert with host and parasite genetics/epigenetics, proteomic/transcriptomic regulation and environmental factors.******Our investigations have focused on characterizing the interface of the cellular and humoral elements of the B. glabrata immune response during challenge by larval S. mansoni. Encapsulation of the parasite by snail immune cells is critical for elimination of the infection. Thus, it is essential for snails to maintain sufficient immune cell populations, to be able to recruit those cells to the parasite surface and have those cells initiate the proper immune effectors to kill the parasite. Our past work touched on each of these elements of a successful response by characterizing the first cellular growth factor in a snail and demonstrating that the cells that develop from stimulation by that growth factor are better suited for killing of S. mansoni. Now, because of this work, we have greater insight into the immune processes taking place within B. glabrata. We also have reagents and bioassays that allow us to investigate snail immune processes with a mechanistic lens. We propose to continue our work characterizing the B. glabrata immune response to S. mansoni challenge by addressing two specific objectives that we have identified as being central to successful parasite clearance by the snail and that build upon our past NSERC DG-supported work:******1. To characterize the process of B. glabrata haemocyte development and to establish the role of specific haemocyte subsets during the cell-mediated anti-schistosome immune response.******2. To investigate the circulating humoral immune factors produced by haemocytes facilitating cell-mediated killing of the larval parasite.