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

Mingshan Xue, Zhiwei Lin, Youli Wen, Shaohui Fan, Youxia Li, Hui-Qi Qu, Qiurong Hu, Qian Guo, Lijun Su, Qianyue Yang, Jiahong Chen, Chuci Jiang, Huimin Huang, Peiyan Zheng, Ning Li, Quan Yuan, Meixia Zhang, Xin Zhao, Qunhua Wu, Fengyu Hu, Lu Li, Xiaowen Wang, Peixin Liu, Hakon Hakonarson, Zhiping Deng, Hongman Wang, Xiaoping Tang and Baoqing Sun ()
Additional contact information
Mingshan Xue: The First Affiliated Hospital of Guangzhou Medical University
Zhiwei Lin: The First Affiliated Hospital of Guangzhou Medical University
Youli Wen: Zigong First People’s Hospital
Shaohui Fan: The Fifth Affiliated Hospital of Zunyi Medical University
Youxia Li: The Fifth Affiliated Hospital of Zunyi Medical University
Hui-Qi Qu: Children’s Hospital of Philadelphia
Qiurong Hu: The First Affiliated Hospital of Guangzhou Medical University
Qian Guo: The First Affiliated Hospital of Guangzhou Medical University
Lijun Su: The First Affiliated Hospital of Guangzhou Medical University
Qianyue Yang: The First Affiliated Hospital of Guangzhou Medical University
Jiahong Chen: The First Affiliated Hospital of Guangzhou Medical University
Chuci Jiang: The First Affiliated Hospital of Guangzhou Medical University
Huimin Huang: The First Affiliated Hospital of Guangzhou Medical University
Peiyan Zheng: The First Affiliated Hospital of Guangzhou Medical University
Ning Li: The First Affiliated Hospital of Guangzhou Medical University
Quan Yuan: Zigong First People’s Hospital
Meixia Zhang: Zigong First People’s Hospital
Xin Zhao: Zigong First People’s Hospital
Qunhua Wu: Zigong First People’s Hospital
Fengyu Hu: Guangzhou Medical University
Lu Li: Guangzhou Medical University
Xiaowen Wang: The Fifth Affiliated Hospital of Zunyi Medical University
Peixin Liu: Zhuhai People’s Hospital
Hakon Hakonarson: Children’s Hospital of Philadelphia
Zhiping Deng: Zigong First People’s Hospital
Hongman Wang: The Fifth Affiliated Hospital of Zunyi Medical University
Xiaoping Tang: The First Affiliated Hospital of Guangzhou Medical University
Baoqing Sun: The First Affiliated Hospital of Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59145-y

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