Reciprocal genetics of recently-evolved vertebrate immunity and peritoneal helminth counter-adaptation

项目摘要/摘要 脊椎动物进化出复杂的免疫系统以消除蠕虫寄生虫的感染 (绦虫、线虫)。然而，蠕虫往往成功地建立了持续性感染，因为 它们进化出了逃避或操纵宿主免疫系统的策略。因为这种寄主寄生虫 共同进化，感染成功取决于宿主免疫基因和寄生虫之间的上位性相互作用 免疫逃避基因。但是，这种上位性的免疫遗传机制仍然很差。 理解，因为大多数研究集中在宿主基因或寄生虫基因对免疫的影响。 与世隔绝。很少有感染的实验模型服从‘互易图谱’--同时遗传 对两个相互作用的物种进行分析。一种小鱼，三刺鱼(Gastersteus Aculeatus)，它的 寄生绦虫(Schistocephalus Solidus)为相互作用提供了一种实验上易于驯化的系统 脊椎动物寄主与寄生虫间跨种上位的遗传分析。 刺鱼的自然种群已经进化出不同程度的抗性，呈现出一种 绘制这些寄主快速进化抗性的基因图谱的机会(线虫消除和 生长抑制)和寄生虫的反适应。我们已经完成了一个初步的数量性状基因座 (QTL)定位寄主对固色链霉菌的抗性。我们的目标1试图改进这张地图以精确定位 有希望的候选基因，然后通过相互作用实验测试这些基因的免疫效果 半身性测试。因为鱼和人类的免疫系统相似，所以在AIM中确定了鱼的免疫基因 1可能会产生人类对蠕虫的抵抗力和相关的免疫紊乱(纤维化，在 特别)。刺鱼免疫的几个基因座只对某些寄生虫基因类型有效， 表明跨物种的上位性正在发生。目标2是相互定位鞭虫基因 寄生虫对宿主免疫反应的变化是潜在的。结合QTL定位，表达QTL 作图和全基因组关联作图(GWAS)，我们打算确定寄生虫的短名单 候选基因。然后，我们将使用相互的半合子测试来实验测试这些寄生虫的基因 对宿主基因表达、免疫特性和感染结果的影响，单独或与宿主基因座上位相关。 寻找寄生虫免疫调节基因可能会揭示治疗蠕虫感染的新方法，或者可能 揭示治疗人类自身免疫性疾病的新疗法。目标3是通过实验验证 寄主表型的保护功能，通过从药理上将寄主基因与寄主分开 表型和检测尾虫适合度的相应变化。最终，我们的目标是确定主机和 共同决定感染成功的寄生虫基因，以了解(I)免疫的机制 腹膜蠕虫感染，(Ii)头虫如何进化以抑制或逃避宿主免疫，以及(Iii) 从而了解我们如何更好地治疗蠕虫感染或相关的免疫病理。

PROJECT SUMMARY/ABSTRACT Vertebrates have evolved sophisticated immune systems to eliminate infections by helminth parasites (tapeworms, nematodes). Nevertheless, helminths often succeed in establishing persistent infections because they have evolved strategies to evade or manipulate their host's immune system. Because of this host-parasite co-evolution, infection success depends on an epistatic interaction between host immune genes and parasites' immune-evasion genes. But, the immunogenetic mechanisms underlying this epistasis remains poorly understood, because most studies focus on immunological effects of either host genes, or parasite genes, in isolation. Few experimental models of infection are amenable to `reciprocal mapping' – the concurrent genetic analysis of both interacting species. A small fish, the threespine stickleback (Gasterosteus aculeatus), and its parasitic tapeworm (Schistocephalus solidus), offer an experimentally tractable system for reciprocal genetic analysis of trans-species epistasis between a vertebrate host and cestode parasite. Natural populations of stickleback have evolved different levels of resistance to S. solidus, presenting an opportunity to map genes underlying these hosts' rapid evolution of resistance (both cestode elimination and growth suppression) and parasite counter-adaptations. We have completed an initial quantitative trait locus (QTL) map of loci underlying host resistance to S. solidus. Our Aim 1 seeks to refine this map to pinpoint promising candidate genes, then experimentally test these genes' immunological effects via reciprocal hemizygosity tests. Because fish and human immune systems are similar, fish immune genes identified in Aim 1 may yield models of human resistance to helminths, and associated immune disorders (fibrosis, in particular). Several loci underlying stickleback immunity are effective only against certain parasite genotypes, demonstrating that trans-species epistasis is occurring. Aim 2 is to reciprocally map cestode genes that underlie variation in the parasites' response to host immunity. By combining QTL mapping, expression QTL mapping, and genome-wide association mapping (GWAS), we intend to identify a short-list of parasite candidate genes. Then, we will use reciprocal hemizygosity tests to experimentally test these parasite genes' effect on host gene expression, immune traits, and infection results, alone or epistatically with host loci. Finding parasite immunomodulation genes may reveal new approaches to treat helminth infections, or may reveal new therapeutic approaches to treat human auto-immune disorders. Aim 3 is to experimentally validate the protective functions of host phenotypes, by pharmacologically separating host genotype from host phenotype and testing for corresponding changes in cestode fitness. Ultimately, our goal is to identify host and parasite genes that jointly determine infection success, to understand (i) mechanisms of immunity to peritoneal helminth infections, (ii) how the cestode evolved to suppress or evade host immunity, and (iii) thereby learn how we might better treat helminth infections or associated immune pathology.