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

最近进化的脊椎动物免疫和腹膜蠕虫反适应的相互遗传学

• 批准号: 10213589
• 负责人: Daniel Imara Bolnick
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213589
• 关键词: Affect; Animal Model; Autoimmune Diseases; Biological Assay; Biological Models; CRISPR/Cas technology; Candidate Disease Gene; Cestoda; Chromosome Mapping; Cohort Studies; Data; Degradation Pathway; Encapsulated; Evolution; Experimental Models; Exposure to; Fibroblasts; Fibrosis; Fishes; Fresh Water; Gasterosteidae; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Screening; Genetic Variation; Genotype; Goals; Growth; Helminths; Home; Host resistance; Human; Immune; Immune Evasion; Immune System Diseases; Immune response; Immune system; Immunity; Immunogenetics; Immunologics; In Vitro; Infection; Learning; Maps; Modeling; Morbidity - disease rate; Nematoda; Outcome; Parasites; Parasitic infection; Pathologic; Pathology; Peritoneal; Peritoneum; Pharmacology; Phenotype; Population; Prevalence; Production; Quantitative Trait Loci; RNA Interference; Race; Research; Resistance; Sclerosis; System; Testing; Vaccination; Variant; Vertebrates; Work; arm; chronic infection; fitness; gene interaction; genetic analysis; genome wide association study; helminth infection; human model; immunoregulation; in vivo; mortality; novel strategies; novel therapeutic intervention; parasite genome; public health relevance; resistance gene; response; side effect; success; targeted treatment; trait; transcriptomics

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.

项目总结/摘要 脊椎动物已经进化出复杂的免疫系统来消除蠕虫寄生虫的感染 （绦虫、线虫）。尽管如此，蠕虫往往成功地建立持续感染，因为 它们进化出了逃避或操纵宿主免疫系统的策略。因为这种寄生虫 共同进化，感染成功取决于宿主免疫基因和寄生虫基因之间的上位相互作用。 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，因为大多数研究都集中在宿主基因或寄生虫基因的免疫学效应上， 隔离很少有感染实验模型能够进行“相互映射”--并发遗传学 分析两个相互作用的物种。一种小鱼，三棘鱼（Gasterosteus aculeatus）， 寄生绦虫（Schistocephalus solidus），提供了一个实验上易于处理的系统， 脊椎动物宿主和绦虫寄生虫之间跨种上位性的遗传分析。 棘鱼的自然种群已经进化出不同程度的抗S。固相线，呈现 有机会绘制这些宿主快速进化抗性的基因（包括绦虫消除和 生长抑制）和寄生虫反适应。我们已经完成了一个初始的数量性状位点 (QTL)寄主对S.固体。我们的目标1试图完善这张地图， 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应， 半合子试验由于鱼类和人类的免疫系统是相似的，鱼类免疫基因在Aim 1可能产生人类抵抗蠕虫的模型，以及相关的免疫疾病（纤维化， 具体）。棘鱼免疫的几个基因座仅对某些寄生虫基因型有效， 这表明跨物种上位性正在发生。目的2是对绦虫基因进行定位， 是寄生虫对宿主免疫力反应变异的基础。结合QTL定位， 定位和全基因组关联定位（GWAS），我们打算确定一个寄生虫的短名单， 候选基因然后，我们将使用相互半合子测试来实验性地测试这些寄生虫基因的功能。 对宿主基因表达、免疫性状和感染结果的影响。 发现寄生虫免疫调节基因可能揭示治疗蠕虫感染的新方法，或者可能 揭示了治疗人类自身免疫疾病的新治疗方法。目标3是通过实验验证 宿主表型的保护功能，通过将宿主基因型与宿主分离， 表型和测试绦虫适应性的相应变化。最终，我们的目标是识别宿主， 共同决定感染成功的寄生虫基因，以了解（i）免疫机制， 腹膜蠕虫感染，（ii）绦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学。