Genetic mechanisms of snail/schistosome compatibility

血吸虫病是迄今为止人类最重要的寄生虫病。疫苗是不可用的， 唯一有效的治疗方法是反复服用一种药物，而耐药性现在是主要的 担忧。血吸虫需要水生蜗牛才能传播。仅大规模药物管理就证明了 在消灭血吸虫病方面效果不佳。现在人们普遍认为，包括以下内容的综合方法 以蜗牛阶段为目标是至关重要的。然而，目前的钉螺控制策略是不可持续的，涉及有毒物质 化学物质或引入捕食者或竞争对手。需要新的方法来打破传播在 蜗牛阶段。了解蜗牛和血吸虫相互作用的分子机制是 寻找新的策略来中断传输。然而，关于软体动物免疫学的知识还远远没有 对钉螺和血吸虫亲和性的分子基础进行了充分和数十年的艰苦研究 只产生了几个候选基因和机制。 BS90是一种高度抗性的光肩星天牛，直到最近，它还被认为是完全 对所有已知的曼氏血吸虫(Sm)菌株具有抵抗力。BS90一直是许多功能的主题 为什么它对Sm感染具有如此抵抗力的研究。因此，找到这种特征背后的基因将是一个主要的 前进。我们最近确定了我们之前使用另一种蜗牛发现的两个基因组区域 涉及到人群，而且还需要绘制一个或多个额外的基因座。 一种Sm菌株可以感染一些BS90钉螺，但在近交的BS90钉螺中存在遗传变异 易感人群。在初步工作中，我们发现，我们命名的一个区域中的一个基因或与之关联的一个基因 PTC2参与了这种耐药基因的多态性。易感的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才能逃避 宿主免疫反应。因此，找到与之相关的蜗牛蛋白可能会导致一个关键的配体 血吸虫来击败BG的免疫反应。 我们将结合使用GWAS和QTL作图方法来缩小(1)剩余的 BS90钉螺的基因组区域，使它们比其他钉螺群体更耐Sm，以及 (2)控制对一株能感染BS90的Sm的易感性的区域/S。我们将对其进行注解和 对每个区域内的候选基因进行排序(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敲除品系测试候选基因。 识别新的抗药性基因将大大提高我们对钉螺-血吸虫的认识 免疫学。我们希望最终能够通过基因操作自然蜗牛种群来制造 它们传播血吸虫的能力较弱。鉴定关键抗病基因并鉴定其功能 将是迈向这一目标的至关重要的第一步。

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.