A new genetic mechanism in snails that controls transmission of schistosomes

蜗牛控制血吸虫传播的新遗传机制

• 批准号: 9120657
• 负责人: Michael Scott Blouin
• 金额: $ 36.31万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120657
• 关键词: Alleles; Amino Acid Sequence; Amino Acids; Bacterial Artificial Chromosomes; Binding; Biomphalaria; Candidate Disease Gene; Chronic; Chronic Disease; Code; Country; Data; Disease; Disease Resistance; Dose; Drug resistance; Ensure; Etiology; Exons; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genetic screening method; Genome; Genomic Segment; Goals; Haplotypes; Health; Helminths; Heterozygote; Human; Immune; Inbreeding; Infection; Malaria; Maps; Medical Economics; Molecular; Organism; Outcome; Parasite Control; Parasites; Parasitic Diseases; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Praziquantel; RNA Interference; Research; Resistance; Resistance to infection; Schistosoma; Schistosoma mansoni; Schistosomatidae; Schistosomiasis; Series; Snails; Specificity; Staging; Testing; Vaccines; Variant; Water; Work; base; disability; disability-adjusted life years; effective therapy; gene function; genetic manipulation; genome wide association study; innovation; interest; knock-down; novel; novel strategies; protein function; resistance gene; transcriptome sequencing; transmission process; whole genome

DESCRIPTION (provided by applicant): Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, the only effective treatment involves repeated dosing with a single drug (praziquantel), and now drug resistance is a major concern. Schistosomes require aquatic snails for transmission. Understanding the molecular mechanisms by which snails and schistosomes interact is key for new strategies to interrupt transmission. Decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just a handful of candidate genes or mechanisms. Using a genome-wide association mapping approach, we recently identified a small region of the genome of the snail, Biomphalaria glabrata, in which allelic variation at an unknown gene has a very strong effect on resistance to Schistosoma mansoni. This region contains 10 putative coding genes, none of which was previously known to be immune relevant in molluscs. The goal of this proposal is to unambiguously identify which of the genes in this region is causal. Firstly, candidate genes will be ranked by their likelihood of being the causal gene. Ranking will be based on whether or not alleles on the resistant versus susceptible haplotypes (versions of the region) differ in (a) expression levels or (b) amino acid sequence, together with information on putative gene function. Then, for each remaining candidate in ranked order, we will functionally test whether allelic variation at that locus actually controls resistance. This will be accomplished using RNA interference (RNAi) and allele-specific RNAi (i.e. knock down one allele or the other in heterozygotes). These complementary approaches allow one to evaluate causality for alleles that differ in either expression level or amino acid sequence. Innovation: Association mapping through functional identification of a causal gene illustrates a fresh new approach in the field of Biomphalaria genetics. The use of inbred lines with RNAseq (whole-genome expression) data, RNAi and allele-specific RNAi in a hypothesis testing framework is also novel. Significance: Identifying new resistance pathways will indicate new ways to potentially interfere with parasite transmission (i.e. how do some snails block schistosomes' ability to detect, penetrate or successfully develop within a host?). Identifying resistance genes in snails is also essential for evaluating whether genetic manipulation of snail populations might become a viable approach for blocking transmission. Understanding resistance in snails should also aid the search for genes in the parasite that control host specificity. Finally, molluscs are intermediate hosts for many diseases of medical and economic importance worldwide. None of the genes in the region of association have been previously identified as immune-relevant in molluscs. Thus, whichever gene turns out to be causal, it will identify a new mechanism of disease resistance in this important group of disease-transmitting organisms.

描述（由申请人提供）：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单一药物（吡喹酮），现在耐药性是一个主要问题。血吸虫需要水生蜗牛传播。了解蜗牛和寄生虫相互作用的分子机制是阻断传播的新策略的关键。几十年来，人们对蜗牛与寄生虫相容性的分子基础进行了艰苦的研究，只找到了少数候选基因或机制。使用全基因组关联映射的方法，我们最近确定了一个小区域的基因组的蜗牛，Biomphalaria glabrata，其中等位基因变异在一个未知的基因有一个非常强大的影响，抗血吸虫曼氏血吸虫。该区域包含10个推定的编码基因，其中没有一个是以前已知的免疫相关的软体动物。这个建议的目的是明确地确定该区域中的哪些基因是因果关系。首先，候选基因将根据其作为因果基因的可能性进行排序。将根据抗性与易感单倍型（区域的版本）上的等位基因是否在（a）表达水平或（B）氨基酸序列方面存在差异以及推定基因功能的信息进行排序。然后，对于按排序的每个剩余候选者，我们将功能性地测试该位点的等位基因变异是否实际上控制抗性。这将使用RNA干扰（RNAi）和等位基因特异性RNAi（即敲低杂合子中的一个等位基因或另一个等位基因）来实现。这些互补的方法允许人们评估在表达水平或氨基酸序列上不同的等位基因的因果关系。创新：通过因果基因的功能鉴定进行关联作图，说明了在遗传学领域的一种新方法。 双脐螺遗传学在假设检验框架中使用具有RNAseq（全基因组表达）数据、RNAi和等位基因特异性RNAi的近交系也是新颖的。重要性：确定新的抗性途径将表明可能干扰寄生虫传播的新方法（即一些蜗牛如何阻止寄生虫体在宿主中检测、穿透或成功发育的能力？）。确定蜗牛中的抗性基因对于评估蜗牛种群的遗传操作是否可能成为阻断传播的可行方法也是必不可少的。了解蜗牛的抗性也有助于寻找寄生虫中控制宿主特异性的基因。最后，软体动物是世界范围内许多具有医学和经济重要性的疾病的中间宿主。在该区域的关联基因中没有一个先前被确定为在软体动物中与免疫相关。因此，无论哪个基因被证明是致病基因，它都将在这一重要的疾病传播生物群中确定一种新的抗病机制。

项目成果

Schistosome infectivity in the snail, Biomphalaria glabrata, is partially dependent on the expression of Grctm6, a Guadeloupe Resistance Complex protein.

• DOI: 10.1371/journal.pntd.0005362
• 发表时间: 2017-02-01
• 期刊: PLOS NEGLECTED TROPICAL DISEASES
• 影响因子: 3.8
• 作者: Allan, Euan R. O.;Tennessen, Jacob A.;Blouin, Michael S.
• 通讯作者: Blouin, Michael S.