SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications. Here, we have evaluated transcriptional and cytokine secretion profiles and detected a distinct upregulation of inflammatory cytokines in infected cell cultures and samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response was mediated by cGAS-STING activation and could be attenuated through several STING-targeting drugs. Our results show that SARS-CoV-2 directs a cGAS-STING mediated, NF-κB-driven inflammatory immune response in human epithelial cells that likely contributes to inflammatory responses seen in patients and could be therapeutically targeted to suppress severe disease symptoms.

SARS-CoV-2 是一种迅速传播的新型病毒，导致全球大流行。在大多数感染患者中，SARS-CoV-2 会导致轻度疾病；然而，在相当大比例的感染中，个体会出现严重的症状，可能导致长期的肺损伤或死亡。这些严重病例通常与高水平的促炎细胞因子和低抗病毒反应有关，这可能导致全身并发症。在这里，我们评估了转录和细胞因子分泌谱，并检测到感染细胞培养物和取自感染患者的样本中炎性细胞因子的明显上调。基于这些观察，我们发现 SARS-CoV-2 感染细胞中 NF-κB 的特异性激活和 IRF3 核易位的阻断。这种 NF-κB 反应是由 cGAS-STING 激活介导的，并且可以通过几种 STING 靶向药物减弱。我们的研究结果表明，SARS-CoV-2 在人类上皮细胞中指导 cGAS-STING 介导的、NF-κB 驱动的炎症免疫反应，这可能导致患者出现炎症反应，并且可以在治疗上靶向抑制严重的疾病症状。