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

1迄今为止，血吸虫病是人类最重要的蠕虫寄生疾病。疫苗不可用， 2唯一有效的治疗方法是用一种药物重复给药，现在耐药性是主要的 3关注。血吸虫需要水生蜗牛进行传输。仅大规模药物管理就证明了 4无效消除血吸虫病。现在被广泛接受的是，包括 5蜗牛控制至关重要。然而，当前的蜗牛控制策略是不可持续的，涉及有毒化学物质或 6个引入的掠食者或竞争者。需要采用新的方法来专注于蜗牛的传播。 7了解蜗牛和血块相互作用的分子机制是寻找新的关键 8个中断传输的策略。然而，关于软体动物免疫学的知识远非足够 从蜗牛 - 尖刺兼容性的分子基础上进行的9年艰苦研究仅产生了 10少数候选基因和机制。使用全基因组关联研究我们最近 11在生物掌lia glabrata的基因组中鉴定出的三个基因组区域，其中等位基因变异很强 12影响对曼森血吸虫的抵抗力。这些区域之一，PB35，对于两个地区特别有趣 13个原因。首先，PB35显示出与观察到的任何基因的抗性最强的等位基因关联 14日期，在两项使用不同种群的寄生虫和蜗牛种群的独立研究中很重要。所以 15该地区的基因在控制血块中可能普遍重要，而不是在公正中很重要 16特定的按应变组合。该地区似乎只有9或10个基因 某些单倍型完全缺少17个。因此，目标1是使用PACBIO完全顺序和注释每个 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特别令人兴奋，因为它将其映射到同一染色体区域作为QTL标记 20两种经过良好的蜗牛菌株BGBS90和BGM线之间的抗性差异。 BGBS90 21对几乎所有经过测试过测试的曼氏菌都具有高度耐药性，而BGM线很容易受到影响，差异 22种隔离为简单的孟德尔特征。几条证据表明，负责的基因 23 BGBS90的极端电阻在PB35区域。 AIM 2将通过重复测试该假设 24反向交叉和标记辅助选择仅交换菌株之间的PB35区域，然后测试是否 25逆转其表型。为什么BGBS90蜗牛对血吸虫具有抗性 26许多功能研究。如果PB35中的基因在该表型背后，那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蜗牛刺激体的了解 28免疫学。总有一天有一天可以将天然蜗牛种群操纵到 29使它们能够传播血吸虫。识别钥匙抗性基因并表征其 30功能将是朝着该目标迈出的重要第一步。 31