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: 8615053
• 负责人: Michael Scott Blouin
• 金额: $ 36.33万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8615053
• 关键词: Alleles; Amino Acid Sequence; Amino Acids; 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; Genome; Genomics; Goals; Haplotypes; 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; public health relevance; transmission process

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.

血吸虫病是迄今为止最重要的人类寄生虫病。疫苗不可用， 唯一有效的治疗方法是用一种药物（praziquantel）重复给药，现在药物 抵抗是一个主要问题。血吸虫需要水生蜗牛进行传输。了解 蜗牛和血块相互作用的分子机制是中断新策略的关键 传播。几十年来，基于蜗牛 - 尖锐体兼容性的分子基础进行了艰苦的研究已有 仅产生少数候选基因或机制。使用全基因组关联映射 方法，我们最近确定了蜗牛基因组的一小部分，生物脑glabrata，其中 未知基因的等位基因变异对对曼森的耐药性具有很强的影响。这 区域包含10个假定的编码基因，以前尚无任何人在 软体动物。该提议的目的是明确确定该地区的哪个基因是因果关系。 首先，候选基因将通过其成为因果基因的可能性进行排名。排名将基于 （a）上的抗性与易感单倍型（版本）上的等位基因是否有所不同 表达水平或（b）氨基酸序列，以及有关假定基因功能的信息。然后，是 每个剩余的候选人按排序顺序排列，我们将在该基因座的功能上测试等位基因的变化 实际控制电阻。这将使用RNA干扰（RNAI）和等位基因特异性RNAi完成 （即，在杂合子中击倒一个等位基因或另一个等位基因）。这些互补方法允许 评估在表达水平或氨基酸序列不同的等位基因的因果关系。创新： 通过因果基因的功能识别映射的关联映射说明了一种新的新方法 遗传学领域。使用RNASEQ（全基因组表达）数据的近交系的使用RNAi 假设检验框架中的等位基因特异性RNAi也是新颖的。意义：确定新的 电阻途径将指出可能干扰寄生虫传播的新方法（即如何 蜗牛阻止了阴茎在宿主中检测，穿透或成功发展的能力？）。识别 蜗牛中的抗性基因对于评估蜗牛种群的遗传操纵也是必不可少的 可能成为阻止传输的可行方法。了解蜗牛的抵抗也应有助于 搜索控制宿主特异性的寄生虫中的基因。最后，软体动物是中间主机 全球许多医学和经济重要性的疾病。关联区域中没有一个基因 以前已被鉴定为软体动物中的免疫相关。因此，任何基因都被证明是因果 它将在这一重要的疾病传播中确定一种新的疾病抗性机制 有机体。