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

识别热点传播区蜗牛媒介的血吸虫病抗性基因：从实验室模型到现场的转化。

• 批准号: 10312036
• 负责人: Michelle L. Steinauer
• 金额: $ 26.27万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312036
• 关键词: Address; Affect; Africa; Africa South of the Sahara; African; Aftercare; Alleles; Area; Biological Models; Biological Sciences; Biomphalaria; Candidate Disease Gene; Chemicals; Child; Control Locus; Disease; Environment; Fresh Water; Future; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genetic Vectors; Genome; Genomic Segment; Genomics; Goals; Habitats; Health; Human; Hygiene; Inbreeding; Individual; Infection; Interruption; Kenya; Knowledge; Laboratories; Measures; Medical; Methods; Modeling; Morbidity - disease rate; Parasites; Persons; Pharmaceutical Preparations; Pharmacotherapy; Population; Poverty; Praziquantel; Predisposition; Production; Proteins; Public Health; Research; Research Personnel; Resistance; Resistance to infection; Resources; Role; Sanitation; Schistosoma; Schistosoma mansoni; Schistosomiasis; Site; Small Interfering RNA; Snails; Source; South America; South American; System; Technology; Testing; Training; Translating; Variant; Water; Work; World Health Organization; base; chronic inflammatory disease; combat; disorder control; experience; genetic resistance; genetic testing; genome sequencing; genome wide association study; genomic tools; global health; improved; knock-down; neglected tropical diseases; novel; offspring; prevent; programs; resistance gene; resistance mechanism; skills; tool; transmission process; vaccine development; vector; vector competence; vector control; virtual; whole genome

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.

项目概要/摘要 血吸虫病仍然是最流行的被忽视的热带病之一，是一种全球健康问题 这种疾病对资源最少的人（即所谓的“底层十亿人”）造成了最大的损失。 事实上，最近的全球估计比 50 年的估计高出 20%。 以前（目前有 2.58 亿病例），血吸虫病在许多流行地区仍然根深蒂固。 世界卫生组织 (WHO) 称，目前 85% 的病例发生在撒哈拉以南非洲地区。 通过大规模药物管理，到 2025 年消除作为公共卫生问题的人类血吸虫病 单一可用药物吡喹酮作为对抗这种寄生虫的主要工具，但是，有一种更综合的药物。 需要采取包括环境卫生、个人卫生、疫苗开发和蜗牛媒介控制在内的方法来实现 这些雄心勃勃的目标旨在利用蜗牛对血吸虫的天然遗传抗性。 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）和血吸虫（Schistosoma mansoni），但大多数是曼氏血吸虫传播 尚不清楚从实验室模型中获得的知识有多少。 因此，为了在遗传上发展，将跨物种传播到自然传播区的非洲蜗牛。 在高流行地区进行基于钉螺的控制，迫切需要确定媒介的遗传机制 我们建议通过联合领域和技术来解决这些野生蜗牛种群的能力。 首先，我们将对野生蜗牛进行全基因组关联研究（GWAS）。 从肯尼亚维多利亚湖的热点传播地点收集的（B. sudanica），以寻找血吸虫抗药性 GWAS 首先发现影响最大的基因——那些最适合血吸虫病的基因。 其次，我们将测试已知影响光滑 B. glabrata 抗性的 8 个基因是否也影响 B. sudanica 的抗性将使用来自自然种群的远交蜗牛和近交系来完成。 鉴定自交系的特征也将为 B. sudanica，这对于候选基因的功能测试至关重要。第三，我们将进行测序和分析。 组装 B. sudanica 的基因组，这不仅有利于我们的 GWAS 和候选基因测试，而且 最后，我们的项目还将解决一个问题。 由于医学软体学专业知识正在下降，因此需要重要的培训。 我们提出的研究将是开发控制措施的第一步。 旨在利用非洲自然发生的遗传变异减少蜗牛与血吸虫相容性的措施 蜗牛处于重要传播区。