Viruses encode secreted and cell-surface expressed proteins essential to modulate host immune defenses and establish productive infections. However, to date there has been no systematic study of the extracellular interactome of any human virus. Here we utilize the E3 proteins, diverse and rapidly evolving transmembrane-containing proteins encoded by human adenoviruses, as a model system to survey the extracellular immunomodulatory landscape. From a large-scale protein interaction screen against a microarray of more than 1,500 human proteins, we find and validate 51 previously unidentified virus-host interactions. Our results uncover conserved strategies as well as substantial diversity and multifunctionality in host targeting within and between viral species. Prominent modulation of the leukocyte immunoglobulin-like and signalling lymphocyte activation molecule families and a number of inhibitory receptors were identified as hubs for viral perturbation, suggesting unrecognized immunoregulatory strategies. We describe a virus-host extracellular interaction map of unprecedented scale that provides new insights into viral immunomodulation.

中文翻译：

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人类腺病毒家族的细胞外相互作用组揭示了多种免疫调节策略。

病毒编码分泌的和细胞表面表达的蛋白，这些蛋白对调节宿主的免疫防御和建立生产性感染至关重要。但是，迄今为止，尚未对任何人类病毒的细胞外相互作用组进行系统研究。在这里，我们利用E3蛋白（人类腺病毒编码的多样化且快速进化的含跨膜蛋白）作为模型系统来调查细胞外免疫调节态势。通过针对1,500多种人类蛋白质的微阵列的大规模蛋白质相互作用筛选，我们发现并验证了51种先前未确定的病毒-宿主相互作用。我们的结果揭示了在病毒物种内部和之间针对宿主的保守策略以及实质性多样性和多功能性。白细胞免疫球蛋白样和信号淋巴细胞激活分子家族和许多抑制性受体的突出调节被确定为病毒摄动的枢纽，表明未认识到的免疫调节策略。我们描述了前所未有的规模的病毒-宿主细胞外相互作用图谱，提供了对病毒免疫调节的新见解。