Table1_Interactome of SARS-CoV-2 Modulated Host Proteins With Computationally Predicted PPIs: Insights From Translational Systems Biology Studies.xlsx

Accelerated efforts to identify intervention strategies for the COVID-19 pandemic caused by SARS-CoV-2 need to be supported by deeper investigations into host invasion and response mechanisms. We constructed the neighborhood interactome network of the 332 human proteins targeted by SARS-CoV-2 proteins, augmenting it with 1,941 novel human protein-protein interactions predicted using our High-precision Protein-Protein Interaction Prediction (HiPPIP) model. Novel interactors, and the interactome as a whole, showed significant enrichment for genes differentially expressed in SARS-CoV-2-infected A549 and Calu-3 cells, postmortem lung samples of COVID-19 patients and blood samples of COVID-19 patients with severe clinical outcomes. The PPIs connected host proteins to COVID-19 blood biomarkers, ACE2 (SARS-CoV-2 entry receptor), genes differentiating SARS-CoV-2 infection from other respiratory virus infections, and SARS-CoV-targeted host proteins. Novel PPIs facilitated identification of the cilium organization functional module; we deduced the potential antiviral role of an interaction between the virus-targeted NUP98 and the cilia-associated CHMP5. Functional enrichment analyses revealed promyelocytic leukaemia bodies, midbody, cell cycle checkpoints and tristetraprolin pathway as potential viral targets. Network proximity of diabetes and hypertension associated genes to host proteins indicated a mechanistic basis for these co-morbidities in critically ill/non-surviving patients. Twenty-four drugs were identified using comparative transcriptome analysis, which include those undergoing COVID-19 clinical trials, showing broad-spectrum antiviral properties or proven activity against SARS-CoV-2 or SARS-CoV/MERS-CoV in cell-based assays. The interactome is available on a webserver at http://severus.dbmi.pitt.edu/corona/.

针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发的COVID-19大流行，加速研发其干预策略的研究亟需依托更深入的宿主入侵与应答机制解析工作作为支撑。本研究构建了受SARS-CoV-2蛋白靶向的332种人类蛋白质的邻域相互作用组网络，并利用本团队开发的高精度蛋白质-蛋白质相互作用预测（HiPPIP）模型预测得到的1941条新型人类蛋白质-蛋白质相互作用对该网络进行了扩充。新型相互作用蛋白及该相互作用组整体均呈现显著富集特性，其富集的差异表达基因分别在SARS-CoV-2感染的A549、Calu-3细胞，COVID-19患者尸检肺组织样本，以及出现严重临床症状的COVID-19患者血液样本中得到验证。蛋白质-蛋白质相互作用（PPIs）将宿主蛋白与COVID-19血液生物标志物、血管紧张素转换酶2（ACE2，SARS-CoV-2入侵受体）、可区分SARS-CoV-2感染与其他呼吸道病毒感染的基因，以及受SARS-CoV靶向的宿主蛋白建立了关联。新型PPIs助力鉴定出纤毛组织功能模块；我们由此推导得到病毒靶向蛋白NUP98与纤毛相关蛋白CHMP5之间的相互作用可能具备抗病毒功能。功能富集分析显示，早幼粒细胞白血病小体、胞质分裂中间体、细胞周期检验点以及三联体促降解蛋白通路可作为潜在的病毒作用靶点。糖尿病与高血压相关基因在宿主蛋白网络中的邻近分布特征，为重症/非存活患者中这类合并症的发生提供了机制层面的依据。本研究通过比较转录组分析共筛选得到24种药物，其中涵盖了正在开展COVID-19临床试验的药物、具备广谱抗病毒特性的药物，以及经细胞实验验证对SARS-CoV-2、SARS-CoV或MERS-CoV具有抑制活性的药物。该相互作用组可通过以下网页服务器获取：http://severus.dbmi.pitt.edu/corona/