VCL/ICAM-1 pathway is associated with lung inflammatory damage in SARS-CoV-2 Omicron infection

作者：Mingshan Xue, Zhiwei Lin, Youli Wen, Susu Fan, Youxia Li, Hui‐Qi Qu, Qiurong Hu, Qian Guo, Lijun Su, Qianyue Yang, Jia-Hong Chen, Chuci Jiang, Huimin Huang, Peiyan Zheng, Ning Li, Quan Yuan, Meixia Zhang, Xin Zhao, Qiyuan Wu, Fengyu Hu, Lu Li, Xiaowen Wang, Peixin Liu, Håkon Håkonarson, Zhiping Deng, Hongman Wang, Xiaoping Tang, Baoqing Sun · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59145-y · 被引用次数：4 · 研究领域：COVID-19 Clinical Research Studies、SARS-CoV-2 and COVID-19 Research、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

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 leak...