Identifying schistosomiasis resistance genes of snail vectors in hotspot transmission zones: Translating from laboratory models to the field.

项目总结/摘要 血吸虫病仍然是最普遍的被忽视的热带病之一，这是一种全球健康问题。 这是一个巨大的威胁，资源最少的人-所谓的“底层十亿人”-付出的代价最大。这种疾病 很难控制事实上，最近的全球估计比50年的估计高出20% 前（目前为2.58亿例）。血吸虫病在许多流行地区仍然根深蒂固， 特别是撒哈拉以南非洲，那里现在发生了85%的病例。世界卫生组织（WHO）呼吁 到2025年消除作为公共卫生问题的人类血吸虫病， 一个单一的可用药物，吡喹酮，作为主要工具，以打击这种寄生虫。然而，一个更完整的 必须采取包括环境卫生、个人卫生、疫苗开发和蜗牛病媒控制在内的方法， 这些雄心勃勃的目标。目前正在研究利用蜗牛对寄生虫的天然遗传抗性的方法， 然而，几乎所有这些研究都使用了南美蜗牛的实验室模型， （Biomphalaria glabrata）和曼氏血吸虫（Schistosoma mansoni），但大多数曼氏血吸虫（S.曼索尼传输 发生在非洲的双脐螺物种中。目前还不清楚从实验室模型中获得的知识有多好 会在自然传播区的非洲蜗牛身上传播。因此，为了从基因上发展 为了在高度流行地区控制钉螺，迫切需要确定媒介的遗传机制， 在这些野生蜗牛种群中的生存能力。我们建议通过一个综合领域来满足这一需求， 基于实验室模型的方法。首先，我们将对野生蜗牛进行全基因组关联研究（GWAS （B.从肯尼亚维多利亚湖的热点传播点收集的苏丹属），以发现耐药性 基因. GWAS首先发现了具有最大效应的基因--那些对血吸虫病最理想的基因 控制其次，我们将测试已知影响B中抗性的8个基因。glabrata也影响 B中的电阻。苏丹。这将使用来自自然种群的远交蜗牛和近交系来完成 来自同一个群体。对近交系的鉴定也将建立B的实验室模型。 苏丹，这将是候选基因的功能测试所必需的。第三，我们将排序， 组装B的基因组。苏丹，这不仅将有助于我们的GWAS和候选基因测试，但 将成为今后病媒控制研究的重要资源。最后，我们的项目还将解决一个 医学软体动物学专业知识正在下降，因此需要重要的培训。这些技能将是必要的， 未来的一些淘汰计划。我们提出的研究将是发展控制的第一步 旨在利用非洲自然发生的遗传变异减少蜗牛与寄生虫相容性的措施 在一个重要的传播区的蜗牛。

PROJECT SUMMARY/ABSTRACT Schistosomiasis continues to be among the most prevalent of Neglected Tropical Diseases, a global health threat, taking the largest toll on those who have the fewest resources—the so-called “bottom billion”. This disease has proven to be difficult to control. Indeed, recent global estimates are 20% higher than estimates of 50 years ago (currently 258 million cases). Schistosomiasis remains stubbornly entrenched in many endemic areas, especially Sub-Saharan Africa where 85% of cases now occur. The World Health Organization (WHO) has called for the elimination of human schistosomiasis as a public health problem by 2025, with mass drug administration of a single available drug, praziquantel, as the main tool to combat this parasite. However, a more integrated approach including sanitation, hygiene, vaccine development and snail vector control will be necessary to reach these ambitious goals. Methods aimed at using natural genetic resistance of snails to schistosomes are being explored; however, almost all of these studies have used laboratory models of South American snails (Biomphalaria glabrata) and schistosomes (Schistosoma mansoni), but the majority of S. mansoni transmission occurs through African species of Biomphalaria. It is unclear how well knowledge gained from laboratory models will translate across species to African snails in natural transmission zones. Thus, in order to develop genetically based snail control in highly endemic areas, there is a critical need to determine genetic mechanisms of vector competence in those wild populations of snails. We propose to address this need through a combined field and laboratory-model based approach. Firstly, we will use a genome wide association study (GWAS) on wild snails (B. sudanica) collected from hotspot transmission sites in Lake Victoria, Kenya, to find schistosome resistance genes. GWAS uncovers genes with the largest effect first—those that are the most ideal for schistosomiasis control. Secondly, we will test whether 8 genes known to influence resistance in B. glabrata also influence resistance in B. sudanica. This will be done using outbred snails from the natural population, and inbred lines derived from the same population. Characterizing the inbred lines will also establish a laboratory model for B. sudanica, which will be essential for functional testing of candidate genes. Thirdly, we will sequence and assemble the genome of B. sudanica, which will not only facilitate our GWAS and candidate gene testing, but will serve as an important resource for future vector-control studies. Finally, our project will also address an important training need as expertise in medical malacology is declining. These skills will be necessary for schistosome elimination programs of the future. Our proposed studies will be the first step in developing control measures aimed at reducing snail-schistosome compatibility using naturally occurring genetic variation in African snails in an important transmission zone.