Aedes aegypti has evolved to become an efficient vector for arboviruses but the mechanisms of host-pathogen tolerance are unknown. Immunoreceptor Toll and its ligand Spaetzle have undergone duplication which may allow neofunctionalization and adaptation. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A complexes that display transient but specific interactions with Spaetzle1C, forming asymmetric complexes, with only one ligand clearly resolved. Loop structures of Spaetzle1C and Toll5A intercalate, temporarily bridging the receptor C-termini to promote signalling. By contrast unbound receptors form head-to-head homodimers that keep the juxtamembrane regions far apart in an inactive conformation. Interestingly the transcriptional signature of Spaetzle1C differs from other Spaetzle cytokines and controls genes involved in innate immunity, metabolism and tissue regeneration. Taken together our results explain how upregulation of Spaetzle1C in the midgut and Toll5A in the salivary gland shape the concomitant immune response.

中文翻译：

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埃及伊蚊 Toll 免疫受体激活的结构和动力学

埃及伊蚊已进化成为虫媒病毒的有效载体但宿主病原体耐受的机制尚不清楚。免疫受体 Toll 及其配体 Spaetzle 经历了复制，这可能允许新功能化和适应。在这里，我们展示了低亲和力 Toll5A 配合物的低温 EM 结构和生物物理特征，这些配合物显示出与 Spaetzle1C 的瞬时但特异性相互作用，形成不对称配合物，只有一个配体清楚地分辨出来。Spaetzle1C 和 Toll5A 的环状结构嵌入，暂时桥接受体 C 末端以促进信号传导。相比之下，未结合的受体形成头对头同源二聚体，使近膜区域在非活性构象中保持相距很远。有趣的是，Spaetzle1C 的转录特征不同于其他 Spaetzle 细胞因子，并控制参与先天免疫、新陈代谢和组织再生的基因。