病毒与宿主的相互作用可以揭示治疗感染的潜在有效和选择性治疗靶点。在这里，我们使用人类 Caco-2 结肠癌细胞作为模型，对病毒复制动态和宿主细胞对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的转录反应进行了综合分析。时间分辨RNA测序显示，感染后，细胞立即转录激活与介导抗病毒反应的炎症途径相关的基因，随后涉及核糖体和线粒体功能的基因表达增加，从而表明蛋白质发生快速改变生产和细胞能量供应。在后期阶段，即感染后 24 至 48 小时之间，参与代谢过程的基因（特别是与外源代谢相关的基因）的表达下降。纳入 SARS-CoV-2 复制的数学模型表明，SARS-CoV-2 蛋白抑制宿主的抗病毒反应，并且病毒转录本超出了宿主细胞的翻译能力。针对宿主细胞中表现出转录增加的激酶依赖性途径，在抑制病毒复制方面与病毒靶向抑制剂一样有效。我们在该模型系统中的发现描绘了 SARS-CoV-2 病毒与宿主相互作用的序列，这可能有助于识别可抑制感染的药物宿主途径。

Virus-host interactions can reveal potentially effective and selective therapeutic targets for treating infection. Here, we performed an integrated analysis of the dynamics of virus replication and the host cell transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using human Caco-2 colon cancer cells as a model. Time-resolved RNA sequencing revealed that, upon infection, cells immediately transcriptionally activated genes associated with inflammatory pathways that mediate the antiviral response, which was followed by an increase in the expression of genes involved in ribosome and mitochondria function, thus suggesting rapid alterations in protein production and cellular energy supply. At later stages, between 24 and 48 hours after infection, the expression of genes involved in metabolic processes-in particular, those related to xenobiotic metabolism-was decreased. Mathematical modeling incorporating SARS-CoV-2 replication suggested that SARS-CoV-2 proteins inhibited the host antiviral response and that virus transcripts exceeded the translation capacity of the host cells. Targeting kinase-dependent pathways that exhibited increases in transcription in host cells was as effective as a virus-targeted inhibitor at repressing viral replication. Our findings in this model system delineate a sequence of SARS-CoV-2 virus-host interactions that may facilitate the identification of druggable host pathways to suppress infection.