Structure-based prediction of West Nile virus-human protein-protein interactions

In recent years, West Nile virus (WNV) has posed a great threat to global human health due to its explosive spread. Studying the protein-protein interactions (PPIs) between WNV and human is beneficial for understanding the pathogenesis of WNV and the immune response mechanism of human against WNV infection at the molecular level. In this study, we identified the human target proteins which interact with WNV based on protein structure similarity, and then the interacting pairs were filtered by the subcellular co-localization information. As a result, a network of 3,346 interactions was constructed, involving 6 WNV proteins and 1970 human target proteins. To our knowledge, this is the first predicted interactome for WNV-human. By analyzing the topological properties and evolution rates of the human target proteins, it was demonstrated that these proteins tend to be the central and bottleneck proteins in the human PPI network and are more conserved than the non-target ones. Triplet analysis showed that the target proteins are adjacent to each other in the human PPI network, suggesting that these proteins may have similar biological functions. Further, the functional enrichment analysis indicated that the target proteins are mainly involved in virus process, transcription regulation, cell adhesion and so on. In addition, the common and specific targets were identified and compared based on the networks between WNV-human and Dengue virus II (DENV2)-human. Finally, by combining topological features and existing drug target information, we identified 30 potential anti-WNV human targets, among which 11 ones were reported to be associated with WNV infection.

近年来，西尼罗河病毒（West Nile virus, WNV）因暴发式传播，对全球人类健康构成严重威胁。研究西尼罗河病毒与人类的蛋白质相互作用（protein-protein interactions, PPIs），有助于从分子层面解析西尼罗河病毒的致病机制，以及人类对抗病毒感染的免疫应答机制。本研究基于蛋白质结构相似性，筛选出与西尼罗河病毒存在相互作用的人类靶蛋白，并通过亚细胞共定位（subcellular co-localization）信息对相互作用对进行过滤。最终构建了包含3346条相互作用的西尼罗河病毒-人类互作网络，涉及6种西尼罗河病毒蛋白与1970种人类靶蛋白。据我们所知，这是首个针对西尼罗河病毒-人类的预测互作组（interactome）。通过分析人类靶蛋白的拓扑属性（topological properties）与进化速率（evolution rates），研究发现此类蛋白在人类蛋白质相互作用网络中多为核心节点与瓶颈蛋白，且较非靶蛋白更为保守。三元组分析（triplet analysis）结果显示，人类靶蛋白在人类蛋白质相互作用网络中彼此相邻，提示这类蛋白可能具有相似的生物学功能。此外，功能富集分析（functional enrichment analysis）表明，人类靶蛋白主要参与病毒相关进程、转录调控、细胞黏附等生物学过程。另外，本研究基于西尼罗河病毒-人类与登革病毒II型（Dengue virus II, DENV2）-人类的互作网络，筛选并比较了二者共有的靶蛋白与特异性靶蛋白。最后，本研究结合拓扑特征与现有药物靶标信息，筛选出30个潜在的抗西尼罗河病毒人类靶蛋白，其中11个已被报道与西尼罗河病毒感染相关。