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

项目摘要/摘要 血吸虫病仍然是最流行的被忽视的热带病之一，这是一个全球健康问题 威胁，对那些拥有最少资源的人--即所谓的“底层10亿”--造成的损失最大。这种病 已经被证明是难以控制的。事实上，最近的全球估计比50年的估计高出20% (目前为2.58亿例)。血吸虫病在许多流行地区仍然顽固地存在， 尤其是撒哈拉以南非洲，现在85%的病例发生在那里。世界卫生组织(WHO)呼吁 到2025年，通过大规模药物管理，消除人类血吸虫病这一公共卫生问题 一种可用的药物，吡喹酮，作为对抗这种寄生虫的主要工具。然而，一个更综合的 将需要采取包括卫生、个人卫生、疫苗开发和控制蜗牛媒介在内的办法来实现 这些雄心勃勃的目标。旨在利用蜗牛对血吸虫的天然遗传抵抗力的方法正在进行中 然而，几乎所有这些研究都使用了南美蜗牛的实验室模型 和血吸虫(曼氏血吸虫)，但曼氏血吸虫传播的大部分 通过非洲种的Biomphalaria发生。目前还不清楚从实验室模型中获得的知识有多好 将跨物种传播到自然传播区的非洲蜗牛。因此，为了从基因上发育 在高度流行地区以灭螺为基础，迫切需要确定媒介的遗传机制 这些野生蜗牛种群的能力。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 从肯尼亚维多利亚湖热点传播点采集的苏丹氏杆菌发现对血吸虫的抵抗力 基因。Gwas首先发现了影响最大的基因--那些对血吸虫病最理想的基因 控制力。其次，我们将测试已知的8个影响光肩星天牛抗性的基因是否也会影响 苏丹花中的抗性。这将使用来自自然种群的异种蜗牛和近交系来完成。 来自相同的人群。对自交系的鉴定也将为B. 这对候选基因的功能测试是必不可少的。第三，我们将按顺序和 组装苏丹芽孢杆菌的基因组，这不仅有助于我们的GWAs和候选基因测试，而且 将成为未来病媒控制研究的重要资源。最后，我们的项目还将解决 由于医学软化学方面的专门知识正在减少，因此需要重要的培训。这些技能对于以下工作是必要的 未来的血吸虫消灭计划。我们提议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降低蜗牛和血吸虫相容性的措施 蜗牛在一个重要的传播区。

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.