COVID-19 (coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the pathophysiology of this virus is complex and largely unknown, we employed a network-biology-fueled approach and integrated transcriptome data pertaining to lung epithelial cells with human interactome to generate Calu-3-specific human-SARS-CoV-2 interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 targets central nodes of the host-viral network, which participate in core functional pathways. Network centrality analyses discover 33 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation, and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host-modifying responses and cytokine storm. Overall, our network-centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into the pathogenicity of SARS-CoV-2 that may help foster effective therapeutic design.

COVID-19（2019年冠状病毒病）是由严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）引起的呼吸系统疾病。尽管该病毒的病理生理学很复杂，并且在很大程度上尚不为人所知，但我们采用了网络生物学驱动的方法，并通过与涉及人类交互基因组的肺上皮细胞整合了转录组数据，以生成Calu-3特异的人类SARS-CoV-2交互基因组（CSI ）。拓扑聚类和途径富集分析表明，SARS-CoV-2靶向宿主病毒网络的中心节点，后者参与了核心功能途径。网络中心性分析发现了33个高价值的SARS-CoV-2靶标，这些靶标可能参与病毒的进入，增殖和存活，以建立感染并促进疾病进展。我们的概率建模框架阐明了与COVID-19相关的关键调控电路和分子事件，尤其是宿主修饰反应和细胞因子风暴。总体而言，我们以网络为中心的分析揭示了新的分子成分，揭示了结构和功能模块，并提供了有关SARS-CoV-2致病性的分子见解，可帮助促进有效的治疗设计。