The Zika virus (ZIKV) and dengue virus (DENV) flaviviruses exhibit similar replicative processes but have distinct clinical outcomes. A systematic understanding of virus–host protein–protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes identified the host proteins required for ZIKV infection and uncovered that proteasome proteins were crucial in this process. Third, high-throughput screening of 6016 bioactive compounds for ZIKV inhibition yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoint proteasomes as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus–host interactions, disease pathogenesis, and new drug targets.
寨卡病毒（ZIKV）和登革热病毒（DENV）同属于黄病毒属（flaviviruses），具有相似的分子结构、复制过程及流行病特征，但感染后的患者却呈现出完全不同的临床症状。系统的构建和解析病毒蛋白组与宿主蛋白质组之间的相互作用网络，对于揭示病毒复制和相关疾病发病机制相关的关键细胞信号通路，以及筛选和鉴定能有效抑制病毒扩增的药物具有重要意义。在本研究中，我们采用了三种独立的系统生物学方法来实现这一目标。首先，利用荧光分子标记每一个重组表达的ZIKV / DENV病毒蛋白，通过与包含有20,240种蛋白的HuProtTM人蛋白质组芯片杂交，筛选和鉴定ZIKV / DENV病毒扩增相关的多种保守细胞信号通路和关键蛋白复合物，其中包括蛋白酶体复合物。其次，利用RNAi技术对10,415个可成药基因（druggable genes）的高通量筛选鉴定ZIKV感染扩增所需的关键宿主蛋白，发现蛋白酶体蛋白在此过程中至关重要。第三，高通量药物筛选技术对6,016种生物活性化合物在抑制ZIKV病毒活性方面进行筛选，鉴定到了134种有效抑制ZIKV和DENV复制的化合物，其中包括六种蛋白酶体抑制剂。综合分析上述多组学技术产生的正交数据集发现蛋白酶体是ZIKV / DENV复制的关键宿主细胞器。本研究为进一步探索黄病毒-宿主相互作用，疾病发病机制和新药靶标提供了丰富的多组学数据集（multi-omics datasets）。





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