Genetic mechanisms of snail/schistosome compatibility

蜗牛/血吸虫相容性的遗传机制

• 批准号: 10311504
• 负责人: Michael Scott Blouin
• 金额: $ 36.75万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2023-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311504
• 关键词: Affect; Alleles; Amino Acids; Backcrossings; Binding; Biomphalaria; Candidate Disease Gene; Chronic; Chronic Disease; Country; Dose; Drug resistance; Genes; Genetic; Genome; Genomic Segment; Goals; Haplotypes; Helminths; Immunology; Inbreeding; Infection; Interruption; Knowledge; Link; Literature; Maps; Molecular; Natural Resistance; Parasites; Parasitic Diseases; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Poison; Population; Quantitative Trait Loci; RNA Interference; Research; Resistance; Schistosoma; Schistosoma mansoni; Schistosomatidae; Schistosomiasis; Snails; Testing; Vaccines; Variant; causal variant; disability; effective therapy; genetic manipulation; genome wide association study; human disease; insertion/deletion mutation; interest; novel strategies; protein function; public health relevance; resistance gene; trait; transmission process; waterborne

1 Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, 2 the only effective treatment involves repeated dosing with a single drug, and now drug resistance is a major 3 concern. Schistosomes require aquatic snails for transmission. Mass drug administration alone has proven 4 ineffective at eliminating schistosomiasis. It is now widely accepted that an integrated approach that includes 5 snail control is essential. Yet current snail control strategies are unsustainable, involving toxic chemicals or 6 introduced predators or competitors. New approaches are needed that focus on transmission by snails. 7 Understanding the molecular mechanisms by which snails and schistosomes interact is key for finding new 8 strategies to interrupt transmission. Yet knowledge about molluscan immunology is far from adequate, and 9 decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just 10 a handful of candidate genes and mechanisms. Using genome-wide association studies we recently 11 identified in the genome of Biomphalaria glabrata three genomic regions in which allelic variation strongly 12 affects resistance to Schistosoma mansoni. One of these regions, PB35, is particularly interesting for two 13 reasons. Firstly, PB35 showed the strongest allelic association with resistance of any gene observed to 14 date, and was significant in two independent studies using different populations of parasites and snails. So 15 the gene in this region may be universally important in controlling schistosomes, rather than important in just 16 a particular strain-by-strain combination. There appear to be only 9 or 10 genes in the region, some of which 17 are completely missing on some haplotypes. So Aim 1 is to use PacBio to fully sequence and annotate each 18 haplotype, and then use RNAi to determine which gene is responsible for the GWAS results. Secondly, 19 PB35 is particularly exciting because it maps to the same chromosomal region as a QTL marker for the 20 dramatic difference in resistance between two well-studied strains of snails, BgBS90 and BgM-line. BgBS90 21 is highly resistant to almost all tested strains of S. mansoni, while BgM-line is susceptible, and the difference 22 segregates as a simple, Mendelian trait. Several lines of evidence suggest the gene responsible for the 23 extreme resistance of BgBS90 is in the PB35 region. Aim 2 will test that hypothesis by using repeated 24 backcrossing and marker-assisted selection to swap just the PB35 region between strains, and then test if 25 that reverses their phenotypes. Why BgBS90 snails are so resistant to schistosomes has been the subject of 26 many functional studies. If the gene in PB35 is behind that phenotype, it will be an important discovery. 27 Identifying new resistance genes will substantially advance our knowledge of snail-schistosome 28 immunology. It is also likely that one could someday genetically manipulate natural snail populations to 29 make them less able to transmit schistosomes. Identifying key resistance genes and characterizing their 30 function would be an essential first step toward that goal. 31

1血吸虫病是迄今为止人类最重要的寄生虫病。疫苗是不可用的， 唯一有效的治疗方法是反复服用一种药物，现在耐药性是主要的 3.担忧。血吸虫需要水生蜗牛才能传播。仅大规模药物管理就证明了 4消灭血吸虫病效果不佳。现在人们普遍认为，包括以下内容的综合方法 5灭螺是必须的。然而，目前的钉螺控制策略是不可持续的，涉及有毒化学品或 6引入捕食者或竞争者。需要以蜗牛传播为重点的新方法。 了解蜗牛和血吸虫相互作用的分子机制是发现新的 中断传播的8种策略。然而，关于软体动物免疫学的知识远远不够，而且 对钉螺和血吸虫亲和性的分子基础进行了90年的艰苦研究，仅取得了 10几个候选基因和机制。利用我们最近进行的全基因组关联研究 光肩星天牛基因组中发现的11个等位基因变异较大的基因组区域 12影响对曼氏血吸虫的抵抗力。其中一个区域，PB35，对两个人来说特别有趣 13个理由。首先，在所观察到的所有基因中，PB35与抗病的等位基因关联最强 14日期，在使用不同寄生虫和蜗牛种群的两项独立研究中具有重要意义。所以 15这一区域的基因在控制血吸虫方面可能普遍重要，而不是仅仅在 16一种特定的菌株间的组合。该区域似乎只有9或10个基因，其中一些 17在某些单倍型上完全缺失。因此，目标1是使用PacBio对每个元素进行完全排序和注释 18单倍型，然后使用RNAi来确定哪个基因对GWAS结果负责。第二， 19 PB35特别令人兴奋，因为它定位到与QTL标记相同的染色体区域 20 BgBS90和BGM-LINE这两个经过充分研究的钉螺品系之间的抵抗力存在显著差异。BgBS90 21对几乎所有的测试菌株都具有高度的抗性，而BGM-line是敏感的，并且差异 22个分离是一个简单的孟德尔特征。几条证据表明，导致这种疾病的基因 23 BgBS90的极端抗性位于PB35区域。目标2将通过使用重复的 24回交和标记辅助选择，仅在品系之间交换PB35区域，然后测试是否 25，这颠倒了他们的表型。为什么BgBS90蜗牛对血吸虫具有如此强的抵抗力 26多项功能研究。如果PB35中的基因是这种表型的幕后推手，这将是一个重要的发现。 27识别新的抗性基因将大大提高我们对钉螺-血吸虫的认识 28免疫学。也有可能有一天，一个人可以通过基因操作自然蜗牛数量来 29使它们传播血吸虫的能力降低。鉴定关键抗病基因并鉴定它们的特性 30功能将是迈向这一目标的重要第一步。 31