The NF-κB Transcriptional Footprint Is Essential for SARS-CoV-2 Replication.
The NF-κB Transcriptional Footprint Is Essential for SARS-CoV-2 Replication.
复制标题
NF-κB转录足迹对SARS-CoV-2复制至关重要
DOI：
10.1128/jvi.01257-21
复制
发表时间：
2021-11-09
影响因子：
5.4
通讯作者：
tenOever BR
中科院分区：
文献类型：
--
作者：
Nilsson-Payant BE;Uhl S;Grimont A;Doane AS;Cohen P;Patel RS;Higgins CA;Acklin JA;Bram Y;Chandar V;Blanco-Melo D;Panis M;Lim JK;Elemento O;Schwartz RE;Rosenberg BR;Chandwani R;tenOever BR
SARS-CoV-2是COVID-19的病原体，其特征在于I型干扰素（IFN-I）介导的抗病毒防御延迟以及强大的细胞因子产生。在此，我们研究了这种不平衡的潜在分子基础，并暗示在缺乏其他典型的IFN-I相关转录因子的情况下，病毒介导的NF-κB活化。表观遗传学和单细胞转录组学分析显示，选择性NF-κB签名在感染细胞中最为突出。通过沉默NF-κB转录因子p65或p50破坏NF-κ B B信号传导导致病毒复制丧失，病毒复制在重建时被挽救。这些发现可以通过使用NF-κB抑制剂得到进一步证实，NF-κB抑制剂可以减少SARS-CoV-2的体外复制。这些数据表明，尽管IFN-I反应减弱，但响应SARS-CoV-2的稳健细胞因子产生是依赖NF-κB进行病毒复制的产物。重要性COVID-19疫情在全球造成重大死亡率及发病率。虽然已经开发出有效的疫苗，但世界上大部分地区仍然没有接种疫苗，而新的SARS-CoV-2变种不断出现。此外，尽管进行了广泛的努力和大规模的药物筛选，但尚未发现完全有效的抗病毒治疗方案。因此，更好地了解驱动SARS-CoV-2复制的基本因素，以便能够开发针对SARS-CoV-2生物学的新方法，是至关重要的。
SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κB inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κB for viral replication. IMPORTANCE The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology.