A Polymorphism in the Processing Body Component Ge-1 Controls Resistance to a Naturally Occurring Rhabdovirus in Drosophila

Hosts encounter an ever-changing array of pathogens, so there is continual selection for novel ways to resist infection. A powerful way to understand how hosts evolve resistance is to identify the genes that cause variation in susceptibility to infection. Using high-resolution genetic mapping we have identified a naturally occurring polymorphism in a gene called Ge-1 that makes Drosophila melanogaster highly resistant to its natural pathogen Drosophila melanogaster sigma virus (DMelSV). By modifying the sequence of the gene in transgenic flies, we identified a 26 amino acid deletion in the serine-rich linker region of Ge-1 that is causing the resistance. Knocking down the expression of the susceptible allele leads to a decrease in viral titre in infected flies, indicating that Ge-1 is an existing restriction factor whose antiviral effects have been increased by the deletion. Ge-1 plays a central role in RNA degradation and the formation of processing bodies (P bodies). A key effector in antiviral immunity, the RNAi induced silencing complex (RISC), localises to P bodies, but we found that Ge-1-based resistance is not dependent on the small interfering RNA (siRNA) pathway. However, we found that Decapping protein 1 (DCP1) protects flies against sigma virus. This protein interacts with Ge-1 and commits mRNA for degradation by removing the 5’ cap, suggesting that resistance may rely on this RNA degradation pathway. The serine-rich linker domain of Ge-1 has experienced strong selection during the evolution of Drosophila, suggesting that this gene may be under long-term selection by viruses. These findings demonstrate that studying naturally occurring polymorphisms that increase resistance to infections enables us to identify novel forms of antiviral defence, and support a pattern of major effect polymorphisms controlling resistance to viruses in Drosophila.

宿主时刻遭遇不断更迭的各类病原体，因此始终面临着演化出全新抗感染策略的选择压力。解析宿主如何演化出抗性的高效途径之一，是甄别那些会导致感染易感性差异的基因。我们借助高分辨率遗传作图技术，在名为Ge-1的基因中发现了一种自然存在的多态性，该多态性可使黑腹果蝇（Drosophila melanogaster）对其自然病原体——黑腹果蝇σ病毒（Drosophila melanogaster sigma virus, DMelSV）展现出极强抗性。通过对转基因果蝇的该基因序列进行改造，我们确定了Ge-1丝氨酸富集连接区中一段26个氨基酸的缺失突变正是该抗性的成因。敲低易感等位基因的表达可降低受感染果蝇体内的病毒载量，这表明Ge-1是一种天然存在的病毒限制因子，其抗病毒效应可通过该缺失得到增强。Ge-1在RNA降解以及加工小体（processing bodies, P bodies）的形成过程中发挥核心作用。作为抗病毒免疫的关键效应分子，RNAi诱导沉默复合体（RNAi induced silencing complex, RISC）会定位于P小体，但我们的研究发现，基于Ge-1的抗性并不依赖于小干扰RNA（small interfering RNA, siRNA）通路。不过我们发现，脱帽蛋白1（Decapping protein 1, DCP1）可保护果蝇免受σ病毒侵染。该蛋白能与Ge-1相互作用，并通过移除mRNA的5’帽子结构使mRNA进入降解流程，这提示抗性的产生或许依赖于这一RNA降解通路。Ge-1的丝氨酸富集连接域在果蝇演化过程中经历了强烈的选择作用，这暗示该基因可能长期处于病毒介导的选择压力之下。上述研究结果表明，对可增强感染抗性的自然多态性展开研究，能够帮助我们发掘全新的抗病毒防御机制，同时也支持了果蝇的病毒抗性由效应显著的多态性调控这一规律。