Biology Department, The Graduate Center, The City College of the City University of New York, New York, New York, United States of America.
PLoS Pathog. 2010 Dec 23;6(12):e1001234. doi: 10.1371/journal.ppat.1001234.
To counter systemic risk of infection by parasitic wasps, Drosophila larvae activate humoral immunity in the fat body and mount a robust cellular response resulting in encapsulation of the wasp egg. Innate immune reactions are tightly regulated and are resolved within hours. To understand the mechanisms underlying activation and resolution of the egg encapsulation response and examine if failure of the latter develops into systemic inflammatory disease, we correlated parasitic wasp-induced changes in the Drosophila larva with systemic chronic conditions in sumoylation-deficient mutants. We have previously reported that loss of either Cactus, the Drosophila (IκB) protein or Ubc9, the SUMO-conjugating enzyme, leads to constitutive activation of the humoral and cellular pathways, hematopoietic overproliferation and tumorogenesis. Here we report that parasite infection simultaneously activates NF-κB-dependent transcription of Spätzle processing enzyme (SPE) and cactus. Endogenous Spätzle protein (the Toll ligand) is expressed in immune cells and excessive SPE or Spätzle is pro-inflammatory. Consistent with this function, loss of Spz suppresses Ubc9⁻ defects. In contrast to the pro-inflammatory roles of SPE and Spätzle, Cactus and Ubc9 exert an anti-inflammatory effect. We show that Ubc9 maintains steady state levels of Cactus protein. In a series of immuno-genetic experiments, we demonstrate the existence of a robust bidirectional interaction between blood cells and the fat body and propose that wasp infection activates Toll signaling in both compartments via extracellular activation of Spätzle. Within each organ, the IκB/Ubc9-dependent inhibitory feedback resolves immune signaling and restores homeostasis. The loss of this feedback leads to chronic inflammation. Our studies not only provide an integrated framework for understanding the molecular basis of the evolutionary arms race between insect hosts and their parasites, but also offer insights into developing novel strategies for medical and agricultural pest control.
为了应对寄生虫黄蜂感染的系统性风险，果蝇幼虫在脂肪体中激活体液免疫，并引发强烈的细胞反应，导致黄蜂卵被包裹。先天免疫反应受到严格调控，并在数小时内得到解决。为了了解卵包被反应的激活和解决的机制，并研究后者的失败是否会发展成系统性炎症性疾病，我们将寄生虫黄蜂诱导的果蝇幼虫变化与泛素化缺陷突变体中的系统性慢性疾病相关联。我们之前曾报道过，缺失果蝇（IκB）蛋白 Cactus 或 SUMO 连接酶 Ubc9，会导致体液和细胞途径的组成性激活、造血过度增殖和肿瘤发生。在这里，我们报告寄生虫感染同时激活了 NF-κB 依赖性 Spätzle 加工酶 (SPE) 和 cactus 的转录。内源性 Spätzle 蛋白（Toll 配体）在免疫细胞中表达，过量的 SPE 或 Spätzle 具有促炎作用。与 SPE 和 Spätzle 的促炎作用一致，Spz 的缺失抑制了 Ubc9⁻缺陷。与 SPE 和 Spätzle 的促炎作用相反，Cactus 和 Ubc9 发挥抗炎作用。我们表明，Ubc9 维持 Cactus 蛋白的稳定状态。在一系列免疫遗传实验中，我们证明了血细胞和脂肪体之间存在强大的双向相互作用，并提出黄蜂感染通过 Spätzle 的细胞外激活在这两个隔室中激活 Toll 信号。在每个器官中，IκB/Ubc9 依赖性抑制反馈解决免疫信号并恢复体内平衡。这种反馈的缺失会导致慢性炎症。我们的研究不仅为理解昆虫宿主与其寄生虫之间的进化军备竞赛的分子基础提供了一个综合框架，也为开发用于医学和农业害虫控制的新策略提供了思路。
