Genetic mechanisms of snail/schistosome compatibility

蜗牛/血吸虫相容性的遗传机制

基本信息

批准号：
10725889
负责人：
Michael Scott Blouin
金额：
$ 37.13万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725889
关键词：
Affect Alleles Binding Biomphalaria Candidate Disease Gene Chronic Chronic Disease Clustered Regularly Interspaced Short Palindromic Repeats Code Country DNA Sequence Data Dose Drug resistance Etiology Generations Genes Genetic Genetic Polymorphism Genetic Variation Genome Scan Genomic Segment Geography Goals Haplotypes Helminths Homozygote Immune response Immunology Inbreeding Individual Infection Interruption Knock-out Knowledge Ligands Link Location Maps Methods Modernization Modification Molecular Names Natural Resistance Parasites Parasitic Diseases Pathway interactions Persons Pharmaceutical Preparations Poison Population Predisposition Quantitative Trait Loci RNA Interference Research Resistance Resistance to infection Schistosoma Schistosoma mansoni Schistosoma mansonii infection Schistosomatidae Schistosomiasis Side Snails Susceptibility Gene System Testing Untranslated RNA Vaccines Variant Work disability effective therapy genetic manipulation genome wide association study human disease novel strategies public health relevance resistance gene resistant strain snail protein trait transcriptome sequencing transmission blocking transmission process waterborne

项目摘要

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, and drug resistance is now a major concern. Schistosomes require aquatic snails for transmission. Mass drug administration alone has proven ineffective at eliminating schistosomiasis. It is now widely accepted that an integrated approach that includes targeting the snail stage is essential. Yet current snail control strategies are unsustainable, involving toxic chemicals or introduced predators or competitors. New approaches are needed to break transmission at the snail stage. Understanding the molecular mechanisms by which snails and schistosomes interact is key for finding new strategies to interrupt transmission. Yet knowledge about molluscan immunology is far from adequate, and decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just a handful of candidate genes and mechanisms. BS90 is a highly resistant strain of Biomphalaria glabrata (Bg) that, until recently, was considered completely resistant to all known strains of Schistosoma mansoni (Sm). BS90 has been the subject of many functional studies of why it is so resistant to infection by Sm. So finding the genes behind that trait would be a major advance. We recently determined that two genomic regions we previously discovered using another snail population are involved, and that one or more additional loci still need to be mapped. One strain of Sm can infect some BS90 snails, but there is genetic variation within the outbred BS90 population for susceptibility. In preliminary work we found that a gene in, or linked to, a region we named PTC2 is involved in this resistance polymorphism. The susceptible haplotype appears to act dominantly, suggesting that some molecule on the parasite side must bind to something on the host side to evade the host immune response. Thus, finding the snail protein involved could lead to a key ligand used by schistosomes to defeat the Bg immune response. We will use a combination of GWAS and QTL mapping approaches to narrow down (1) the remaining genomic regions in BS90 snails that make them more resistant to Sm than other populations of snails, and (2) the region/s that control susceptibility to the one strain of Sm that can infect BS90. We will annotate and rank candidate genes within each region (based on predicted function and on sequence or expression difference between haplotypes). Then test candidate genes using RNAi and/or CRISPR knock-out lines. Identifying new resistance genes will substantially advance our knowledge of snail-schistosome immunology. We hope to eventually be able to genetically manipulate natural snail populations to make them less able to transmit schistosomes. Identifying key resistance genes and characterizing their function will be an essential first step toward that goal.

血吸虫病是迄今为止人类最重要的蠕虫寄生虫病。疫苗没有了，唯一有效的治疗方法是重复服用单一药物，而耐药性现在是一个主要问题忧虑。血吸虫需要水生蜗牛进行传播。仅大规模药物管理就已证明对消除血吸虫病无效。现在人们普遍认为综合方法包括针对蜗牛阶段至关重要。然而，目前的蜗牛控制策略是不可持续的，涉及有毒物质化学品或引入的掠食者或竞争对手。需要新的方法来阻断传播蜗牛阶段。了解蜗牛和血吸虫相互作用的分子机制是关键寻找新的策略来中断传播。然而，关于软体动物免疫学的知识还远远不够。对蜗牛与血吸虫相容性的分子基础进行了充分的、数十年的潜心研究仅产生了少数候选基因和机制。 BS90 是光滑双脐 (Bg) 的一种高度耐药菌株，直到最近，它还被认为是完全耐药的。对所有已知的曼氏血吸虫 (Sm) 菌株具有抗药性。 BS90 已成为许多功能的主题研究为什么它对 Sm 感染具有如此的抵抗力。因此，找到该特征背后的基因将是一个重要的任务进步。我们最近确定了我们之前使用另一只蜗牛发现的两个基因组区域涉及人口，并且仍需要绘制一个或多个额外基因座。一种 Sm 菌株可以感染一些 BS90 蜗牛，但远交的 BS90 内存在遗传变异人群的易感性。在初步工作中，我们发现一个位于我们命名的区域中或与之相关的基因 PTC2 参与了这种抗性多态性。易感单倍型似乎占主导地位，这表明寄生虫一侧的某些分子必须与宿主一侧的某些分子结合才能逃避宿主免疫反应。因此，找到所涉及的蜗牛蛋白可能会导致找到一个关键配体，该配体被血吸虫可以击败 Bg 免疫反应。我们将结合使用 GWAS 和 QTL 作图方法来缩小 (1) 剩余的范围 BS90 蜗牛的基因组区域使它们比其他蜗牛种群对 Sm 具有更强的抵抗力，以及 (2)控制对可感染BS90的一种Sm菌株的易感性的区域。我们将注释并对每个区域内的候选基因进行排名（基于预测的功能和序列或表达）单倍型之间的差异）。然后使用 RNAi 和/或 CRISPR 敲除系测试候选基因。识别新的抗性基因将大大增进我们对蜗牛血吸虫的了解免疫学。我们希望最终能够通过基因操纵自然蜗牛种群来制造他们传播血吸虫的能力较差。识别关键抗性基因并表征其功能将是实现这一目标的重要第一步。