Xue Mingshan, Lin Zhiwei, Wen Youli, Fan Shaohui, Li Youxia, Qu Hui-Qi, Hu Qiurong, Guo Qian, Su Lijun, Yang Qianyue, Chen Jiahong, Jiang Chuci, Huang Huimin, Zheng Peiyan, Li Ning, Yuan Quan, Zhang Meixia, Zhao Xin, Wu Qunhua, Hu Fengyu, Li Lu, Wang Xiaowen, Liu Peixin, Hakonarson Hakon, Deng Zhiping, Wang Hongman, Tang Xiaoping, Sun Baoqing
Department of Clinical Laboratory, National Center for Respiratory Medicine / National Clinical Research Center for Respiratory Disease / Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, 510000, China.
Nat Commun. 2025 Apr 23;16(1):3801. doi: 10.1038/s41467-025-59145-y.
SARS-CoV-2 variants present diverse clinical manifestations, necessitating deeper insights into their pathogenic effects. This study employs multi-omics approaches to investigate the molecular mechanisms underlying SARS-CoV-2 infection, focusing on vascular damage. Plasma proteomic analysis of unvaccinated participants infected with Omicron BA.2.76 or ancestral variants identifies key signaling pathways associated with endothelial dysfunction, with the vinculin (VCL) pathway emerging as a hallmark of Omicron infections, contributing to lung exudation. Metabolomic analysis of plasma samples from the same cohort reveals disruptions in immune function, cell membrane integrity, and metabolic processes, including altered tricarboxylic acid cycle and glycolysis pathways. An integrated analysis of proteomic and metabolomic data underscores the role of VCL in inflammation and extravasation, highlighting its interactions with adhesion molecules and inflammatory metabolites. A validation cohort of plasma samples from Omicron-infected participants confirms this association by replicating proteomic analysis, showing elevated VCL levels correlated with inflammatory markers. Functional studies in a male rat model of lung injury demonstrate that anti-VCL intervention reduces plasma VCL levels, mitigates alveolar edema, and restores alveolar-capillary barrier integrity, as assessed by histological staining and electron microscopy, thereby illustrating VCL modulation's impact on vascular leakage and extravasation. These findings establish VCL as a potential therapeutic target for mitigating vascular complications in SARS-CoV-2 infections.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体呈现出多样的临床表现，因此有必要更深入地了解其致病作用。本研究采用多组学方法来探究SARS-CoV-2感染背后的分子机制，重点关注血管损伤。对感染奥密克戎BA.2.76或原始变体的未接种疫苗参与者进行血浆蛋白质组分析，确定了与内皮功能障碍相关的关键信号通路，其中纽蛋白（VCL）通路成为奥密克戎感染的一个标志，导致肺部渗出。对同一队列的血浆样本进行代谢组分析，揭示了免疫功能、细胞膜完整性和代谢过程的破坏，包括三羧酸循环和糖酵解途径的改变。蛋白质组学和代谢组学数据的综合分析强调了VCL在炎症和血管外渗中的作用，突出了其与黏附分子和炎症代谢物的相互作用。来自奥密克戎感染参与者的血浆样本验证队列通过重复蛋白质组分析证实了这种关联，显示VCL水平升高与炎症标志物相关。在雄性大鼠肺损伤模型中的功能研究表明，抗VCL干预可降低血浆VCL水平，减轻肺泡水肿，并通过组织学染色和电子显微镜评估恢复肺泡-毛细血管屏障的完整性，从而说明了VCL调节对血管渗漏和血管外渗的影响。这些发现确立了VCL作为减轻SARS-CoV-2感染血管并发症的潜在治疗靶点。
