Genetic mechanisms of snail/schistosome compatibility

蜗牛/血吸虫相容性的遗传机制

• 批准号: 10078938
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078938
• 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; 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

血吸虫病是迄今为止人类最重要的蠕虫寄生虫病。没有疫苗， 唯一有效的治疗方法是重复服用一种药物，现在耐药性是一个主要的问题。 3关注。血吸虫需要水生蜗牛传播。单是大规模药物管理就证明了 4例血吸虫病防治效果不佳。现在人们普遍认为，一种综合办法， 五是控制疫情至关重要。然而，目前的蜗牛控制策略是不可持续的，涉及有毒化学品或 6引入捕食者或竞争对手。需要新的方法来关注蜗牛的传播。 7了解蜗牛和寄生虫相互作用的分子机制是寻找新的 8策略中断传输。然而，关于软体动物免疫学的知识还远远不够， 在蜗牛与寄生虫相容性的分子基础上进行了长达90年的艰苦研究， 10少数候选基因和机制。利用全基因组关联研究，我们最近 11在光滑双脐螺的基因组中确定了三个基因组区域，其中等位基因变异强烈 12影响对曼氏血吸虫的抵抗力。其中一个区域，PB35，对于两个 13个理由首先，PB35显示出与观察到的任何基因的抗性的最强等位基因关联， 14日，并在两个独立的研究中使用不同的寄生虫和蜗牛的人口显着。所以 该区域的基因可能在控制染色体中普遍重要，而不仅仅是在控制染色体中重要。 16一个特定的菌株一个菌株的组合。在这个区域似乎只有9或10个基因，其中一些基因 17个在某些单倍型上完全缺失。因此，目标1是使用PacBio对每个序列进行完整排序和注释 18单倍型，然后使用RNAi来确定哪个基因负责GWAS结果。第二、 19 PB35是特别令人兴奋的，因为它定位到与QTL标记相同的染色体区域， 在两种研究充分的蜗牛品系BgBS 90和BgM系之间的抗性存在显著差异。BgBS 90 21号对几乎所有供试菌株都具有高抗性。mansoni，而BgM系是感病的， 22分离作为一个简单的，孟德尔性状。有几条证据表明， 23. BgBS 90的极端抗性在PB 35区域。目标2将通过使用重复的 24回交和标记辅助选择，以在菌株之间仅交换PB35区域，然后测试 25种基因突变。为什么BgBS90蜗牛对嗜热小体具有如此强的抵抗力， 26篇功能性研究如果PB35中的基因是这种表型的背后，这将是一个重要的发现。 鉴定新的抗性基因将大大提高我们对蜗牛寄生虫的认识。 28免疫学也有可能有一天，人们可以通过基因操纵自然蜗牛种群， 29使他们不太能够传播病毒。确定关键抗性基因并表征其 30项职能将是实现这一目标的重要的第一步。 31