Reciprocal genetics of recently-evolved vertebrate immunity and 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，蠕虫往往能够成功地建立持续性感染。 因为它们进化出了逃避或操纵宿主免疫系统的策略。因为这位主持人- 寄生虫的共同进化，感染的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，潜在的免疫遗传机制 这种物种间的上位性仍然知之甚少，因为大多数研究都集中在免疫学上。 寄主基因或寄生虫基因的影响分别进行了研究。很少有感染的实验模型是 服从‘相互作图’--两个相互作用的物种的同时遗传分析。一小块 三刺鱼及其寄生的绦虫(Schistocephalus) Solidus)，为反式遗传分析提供了一种实验上易操作的系统。 脊椎动物宿主和线虫寄生虫之间的物种上位性。一些自然种群 刺鱼进化出对绦虫感染的侵袭性炎症反应，从而限制了绦虫 生长和存活，但会导致严重和持续的全身体腔纤维化，这是一种新的模型 用于人体包裹性腹膜硬化症。虽然这是抵抗感染的有效防御措施，但这种纤维化 也是病态的，限制了鱼类的流动性和繁殖力。为了改善这种病理，一些人 刺鱼种群进化出了非凡的恢复能力，部分逆转了早期的纤维化。其他 种群进化出一种耐受策略，通过在开始时抑制纤维化来允许绦虫生长 感染；但当纤维化确实发生时，这些基因型别无法逆转纤维化。目标1是确定 刺鱼种群之间自然进化的纤维化发生速度差异的遗传基础， 最严重的，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 测绘、种群基因组学和实验进化。将使用CRISPR/CAS9编辑来确认 定位基因的表型效应。然而，纤维化也是遗传性的表型结局。 寄生虫种群之间的差异。因此，目标2是识别调节宿主的绦虫基因 纤维化反应，使用QTL定位、群体基因组学和实验性基因编辑。目标3 合并AIMS 1和2的结果，以测试物种间的上位性交互作用(宿主之间的协同作用 和寄生虫基因)调节纤维化的开始、严重和逆转。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或 抑制，以了解(I)对腹膜蠕虫感染的免疫机制，(Ii)如何 鞭虫进化为抑制或逃避宿主免疫，以及(Iii)发病时潜在的变异基因， 严重程度，以及从纤维化中恢复，这既是免疫适应性的，也是病理的。

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.