Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Int J Mol Sci. 2024 Jan 18;25(2):1157. doi: 10.3390/ijms25021157.
The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target.
2019 年冠状病毒病（COVID-19）大流行是现代全球首要的公共卫生挑战。呼吸道是严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的主要靶标，大量细胞死亡和肺部损伤是暴露的标志性特征。导致细胞死亡和肺部损伤的病毒因素仍不完全清楚。因此，本研究调查了病毒辅助蛋白开放阅读框 7b（Orf7b）在引起肺部损伤中的作用。在筛选病毒蛋白时，我们确定 Orf7b 是介导肺上皮细胞死亡的主要病毒因子之一。Orf7b 的过表达导致肺上皮细胞凋亡和铁死亡，凋亡和铁死亡抑制剂可消除 Orf7b 诱导的细胞死亡。Orf7b 上调转录调节剂 c-Myc，c-Myc 是激活肺细胞死亡途径所必需的。c-Myc 的耗竭可减轻 COVID-19 暴露引起的凋亡和铁死亡以及肺部损伤。我们的研究表明，Orf7b 在 COVID-19 暴露引起的细胞死亡和肺部损伤中起主要作用，支持其作为一种潜在的治疗靶点。
