Genetic mechanisms of snail/schistosome compatibility

蜗牛/血吸虫相容性的遗传机制

• 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
• 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

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。没有疫苗， 唯一有效的治疗方法是重复服用单一药物，而耐药性现在是主要的治疗方法。 关心血吸虫需要水生蜗牛传播。单是大规模药物管理就证明了 对消灭血吸虫病无效。现在人们普遍认为，一种综合办法， 针对蜗牛阶段是至关重要的。然而，目前的蜗牛控制策略是不可持续的， 化学物质或引入的捕食者或竞争对手。需要新的方法来阻断 蜗牛阶段了解蜗牛和寄生虫相互作用的分子机制是 寻找新的策略来阻断传播然而，关于软体动物免疫学的知识还远没有 足够的，和几十年的艰苦研究的分子基础上的蜗牛， 只发现了少数候选基因和机制。 BS 90是光滑双脐螺（Bg）的一个高抗性菌株，直到最近， 对曼氏血吸虫（Sm）的所有已知菌株具有抗性。BS 90已经成为许多功能的主题 研究为什么它对Sm的感染如此抵抗。因此，找到这种特征背后的基因将是一个主要的 提前我们最近确定，我们以前用另一种蜗牛发现的两个基因组区域， 群体，并且仍需要绘制一个或多个额外的基因座。 一株Sm能感染部分BS 90钉螺，但在远交系BS 90内存在遗传变异 人群的易感性。在初步工作中，我们发现，一个基因，或连接到一个区域，我们命名为 PTC 2参与了这种耐药多态性。易感单倍型似乎起主导作用， 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，以逃避寄生虫的攻击。 宿主免疫反应因此，找到蜗牛蛋白可能会导致一个关键的配体， Bg免疫反应的抑制剂。 我们将使用GWAS和QTL作图方法的组合来缩小（1）剩余的 BS 90蜗牛中的基因组区域使它们比其他蜗牛种群对Sm更具抗性，以及 (2)控制对可感染BS 90的Sm菌株的敏感性的区域。我们将进行注释， 对每个区域内的候选基因进行排名（基于预测的功能以及序列或表达 haplotypes之间的差异）。然后使用RNAi和/或CRISPR敲除系测试候选基因。 鉴定新的抗性基因将大大提高我们对蜗牛寄生虫的认识。 免疫学我们希望最终能够通过基因操纵自然蜗牛种群， 它们就不太能传播寄生虫。鉴定关键抗性基因并表征其功能 将是实现这一目标的重要的第一步。

项目成果

PTC2 region genotypes counteract Biomphalaria glabrata population differences between M-line and BS90 in resistance to infection by Schistosoma mansoni.

• DOI: 10.7717/peerj.13971
• 发表时间: 2022
• 期刊: PEERJ
• 影响因子: 2.7
• 作者: Blouin, Michael S.;Bollmann, Stephanie R.;Tennessen, Jacob A.
• 通讯作者: Tennessen, Jacob A.

Heat shock increases hydrogen peroxide release from circulating hemocytes of the snail Biomphalaria glabrata.

• DOI: 10.1016/j.fsi.2020.07.029
• 发表时间: 2020-10
• 期刊: Fish & shellfish immunology
• 影响因子: 4.7
• 作者: Allan ERO;Blouin MS
• 通讯作者: Blouin MS