人类疱疹病毒感染无处不在,并在全球范围内引起公共卫生关注。目前的治疗方法降低了与疱疹感染相关的一些症状的严重程度,但既不能从感染宿主中清除病毒库,也不能保护其免受疱疹感染特征的反复症状爆发。治疗这些病毒系统的困难部分源于它们非常大的蛋白质组以及它们定制的复杂的物理和功能关联网络。这项研究提出了我们的努力,以解开1型单纯疱疹病毒相互作用的复杂性(HSV1),典型的疱疹病毒物种。受我们以前工作的启发,我们为HSV1中的蛋白质-蛋白质相互作用(PPI)网络重建提供了一种改进的,更集成的计算管道,以及新开发的共识聚类框架,这使我们能够将分析扩展到二元物理相互作用之外,并揭示了病毒体蛋白质组中高阶功能关联的系统级布局。此外,该分析为目前特征不足的蛋白pUS10提供了新的功能注释.深入的生物信息学序列分析揭示了pUS10中的结构特征,让人想起在尾噬菌体中一些衣壳相关蛋白中观察到的结构特征,疱疹病毒被认为有着共同的祖先。使用免疫亲和纯化(IP)-质谱(MS),我们获得了对我们的生物信息预测之间的相互作用pUS10和内膜蛋白pUL37,其结合细胞溶质衣壳的额外支持,有助于最初的实验和最终的病毒体成熟。总之,这项研究揭示了新的,根据我们的知识,在系统和分子水平上的见解,可以帮助我们更好地了解疱疹病毒感染背后的复杂性。
Infections with human herpesviruses are ubiquitous and a public health concern worldwide. Current treatments reduce the severity of some symptoms associated to herpetic infections but neither remove the viral reservoir from the infected host nor protect from the recurrent symptom outbreaks that characterise herpetic infections. The difficulty in therapeutically tackling these viral systems stems in part from their remarkably large proteomes and the complex networks of physical and functional associations that they tailor. This study presents our efforts to unravel the complexity of the interactome of herpes simplex virus type 1 (HSV1), the prototypical herpesvirus species. Inspired by our previous work, we present an improved and more integrative computational pipeline for the protein-protein interaction (PPI) network reconstruction in HSV1, together with a newly developed
consensus clustering framework, which allowed us to extend the analysis beyond binary physical interactions and revealed a system-level layout of higher-order functional associations in the virion proteome. Additionally, the analysis provided new functional annotation for the currently undercharacterised protein pUS10. In-depth bioinformatics sequence analysis unravelled structural features in pUS10 reminiscent of those observed in some capsid-associated proteins in tailed bacteriophages, with which herpesviruses are believed to share a common ancestry. Using immunoaffinity purification (IP)-mass spectrometry (MS), we obtained additional support for our bioinformatically predicted interaction between pUS10 and the inner tegument protein pUL37, which binds cytosolic capsids, contributing to initial tegumentation and eventually virion maturation. In summary, this study unveils new, to our knowledge, insights at both the system and molecular levels that can help us better understand the complexity behind herpesvirus infections.