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

最近进化的脊椎动物免疫和蠕虫反适应的相互遗传学

• 批准号: 10658506
• 负责人: Daniel Imara Bolnick
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658506
• 关键词: Adjuvant; Affect; Animals; Attenuated; Biological Models; Breeding; CRISPR/Cas technology; Cestoda; Cestode Infections; Chromosome Mapping; Chronic; Cicatrix; Clustered Regularly Interspaced Short Palindromic Repeats; Cohort Studies; Collagen; Disease; Encapsulated; Evolution; Exhibits; Experimental Models; Extracellular Matrix; Fertility; Fibrinogen; Fibrosis; Fishes; Fresh Water; Gasterosteidae; Genes; Genetic; Genetic Epistasis; Genetic Screening; Genetic Variation; Genomics; Genotype; Geography; Goals; Growth; Helminths; Heritability; Host resistance; Human; Hybrids; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunogenetics; Immunologics; Infection; Inflammation; Inflammatory Response; Injections; Intraperitoneal Injections; Lesion; Maps; Modeling; Morbidity - disease rate; Nematoda; Outcome; Parasites; Pathologic; Pathology; Pathway interactions; Peritoneal; Peritoneum; Phenotype; Population; Proteins; Proteomics; Quantitative Trait Loci; Recording of previous events; Recovery; Reproduction; Research; Resistance; Risk; Sclerosis; Severities; Speed; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Variant; Vertebrates; Work; aluminum sulfate; arms race; attenuation; body cavity; chronic infection; cost; genetic analysis; genome wide association study; helminth infection; model organism; mortality; parasite genome; public health relevance; response; success; synergism; systems research; theories; tool; trait; transcriptomics

PROJECT SUMMARY/ABSTRACT Vertebrates evolved sophisticated immune systems to eliminate infections by helminth parasites (tapeworms, nematodes). Nevertheless, helminths often succeed in establishing persistent infections because they evolved strategies to evade or manipulate their host’s immune system. Because of this host- parasite co-evolution, infection success is expected to depend on an epistatic interaction between host immune genes and parasites’ immune-evasion genes. But, the immunogenetic mechanisms underlying this between-species epistasis remains poorly understood, because most studies focus on immunological effects of either host genes, or parasite genes, studied separately. 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. Some natural populations of stickleback evolved an aggressive inflammatory response to tapeworm infection that limits tapeworm growth and survival, but results in severe and persistent fibrosis throughout the body cavity, a new model for human Encapsulating Peritoneal Sclerosis. Although an effective defense against infection, this fibrosis is also pathological, limiting fish mobility and reproduction. To ameliorate this pathology, some stickleback populations evolved a remarkable capacity to recover, partially reversing earlier fibrosis. Other populations evolved a tolerance strategy, allowing tapeworm growth by suppressing fibrosis at the start of infection; but these genotypes are unable to reverse fibrosis when it does occur. Aim 1 is to identify the genetic basis of naturally-evolved variation among stickleback populations in the speed of fibrosis onset, maximum severity, and reversal. We will achieve this using a triangulation approach merging QTL linkage mapping, population genomics, and experimental evolution. CRISPR/cas9 editing will be used to confirm the phenotypic effect of mapped genes. However, fibrosis is also a phenotypic outcome of heritable differences between parasite populations. So, Aim 2 is to identify tapeworm genes that modulate the host fibrosis response, using QTL mapping, population genomics and experimental gene editing. Aim 3 merges the results of Aims 1&2, to test for between-species epistatic interactions (synergy between host and parasite genes) regulating onset, severity, and reversal of fibrosis. Ultimately, our goal is to identify host and parasite genes that jointly determine infection success, and influence fibrosis severity or suppression, to understand (i) mechanisms of immunity to peritoneal helminth infections, (ii) how the cestode evolved to suppress or evade host immunity, and (iii) the genes underlying variation in onset, severity, and recovery from fibrosis that is both immunologically adaptive but also pathological.

项目总结/摘要 脊椎动物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。因为这个主持人- 寄生虫共同进化，感染成功预计取决于宿主之间的上位相互作用 免疫基因和寄生虫的免疫逃避基因。但是， 这种种间上位性仍然知之甚少，因为大多数研究集中在免疫学上， 无论是宿主基因的影响，或寄生虫基因，分别研究。很少有感染的实验模型 适合于“相互映射”--对两个相互作用的物种进行同时的遗传分析。一个小 三棘鱼（Gasterosteus aculeatus）及其寄生绦虫（Schistocephalus solidus），提供了一个实验上易处理的系统，用于反式- 脊椎动物宿主和绦虫寄生虫之间的种间上位。一些自然种群 棘鱼进化出一种对绦虫感染的侵略性炎症反应， 生长和存活，但导致整个体腔严重和持续的纤维化，这是一种新的模型， 人类包裹性腹膜硬化症尽管这种纤维化是对抗感染的有效手段， 也是病理性的，限制了鱼类的流动性和繁殖。为了改善这种病理，一些 棘鱼种群进化出了惊人的恢复能力，部分逆转了早期的纤维化。其他 种群进化出了一种耐受策略，通过在开始时抑制纤维化来允许绦虫生长。 感染;但这些基因型不能逆转纤维化时，它确实发生。目标1是确定 刺鱼种群在纤维化发病速度方面自然进化变异的遗传基础， 最大的严重性和逆转。我们将使用合并QTL连锁的三角测量方法来实现这一点 地图绘制、群体基因组学和实验进化。CRISPR/cas9编辑将用于确认 定位基因的表型效应。然而，纤维化也是遗传性纤维化的表型结果。 寄生虫种群之间的差异。因此，目标2是鉴定调节宿主的绦虫基因 纤维化反应，使用QTL作图，群体基因组学和实验基因编辑。目标3 合并目的1和2的结果，以测试种间上位相互作用（宿主之间的协同作用）。 和寄生虫基因）调节纤维化的发生、严重程度和逆转。最终，我们的目标是确定 宿主和寄生虫基因共同决定感染成功，并影响纤维化严重程度， 抑制，了解（一）免疫机制腹膜蠕虫感染，（二）如何 绦虫进化为抑制或逃避宿主免疫，和（iii）发病变异的基因， 严重程度和从纤维化中恢复，这既是免疫适应性的，也是病理性的。