Regulatory Role of the VCL/ICAM-1 Pathway in Inflammatory Exudative Damage to the Gas-Blood Barrier in SARS-CoV-2 Infection: New Insights from the Omicron Paradigm

Infections by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from the initial Wildtype (WT) variant in Wuhan, China, to later variants including Omicron, have showcased a diverse spectrum of symptoms. This diversity underscores the need for ongoing exploration into the virus's elusive pathogenesis. This study employs multi-omics and collaborative validation methods to comprehensively understand SARS-CoV-2's pathology, offering insights that remain pertinent as the virus evolves. Through proteomic analysis, we have identified signaling pathways associated with damage to the vascular system. Importantly, the vinculin (VCL) pathway has been identified as a distinctive feature in Omicron infections, representing a key mechanism causing lung exudation. Metabolomic analysis uncovered disruptions in immune functions, cell membrane stability, and metabolic shifts. Integrated analysis highlighted the involvement of VCL in processes such as inflammation, cell adhesion, and extravasation. A validation cohort confirmed VCL and ICAM1 as Omicron-associated biomarkers. Our mouse model studies not only corroborated these findings but also indicated therapeutic potential of targeting VCL. In contrast to genomic studies highlighting host immunity and infection susceptibility in COVID-19, our research sheds light on the evolving physiological impacts induced by the Omicron variant via the VCL pathway. By our elucidation of key molecular mechanisms involved, provides a strategic direction for developing therapies to address emerging SARS-CoV-2 variants, emphasizing the need for continuous adaptation in combating viral challenges.

严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）感染可呈现多样化的症状谱，其致病毒株范围涵盖最初在中国武汉发现的野生型（Wildtype, WT）变异株，直至后续包括奥密克戎（Omicron）在内的各类变异株。这种多样性凸显了持续探究该病毒隐匿致病机制的迫切需求。本研究采用多组学（multi-omics）与协同验证方法，以全面解析SARS-CoV-2的致病机理，相关研究结论在病毒持续演化的当下仍具有重要参考价值。通过蛋白质组学分析（proteomic analysis），本研究鉴定出与血管系统损伤相关的信号通路；尤为关键的是，黏着斑蛋白（vinculin, VCL）通路被确定为奥密克戎感染的特征性通路，其是引发肺渗出的核心机制之一。代谢组学分析（metabolomic analysis）则揭示了免疫功能紊乱、细胞膜稳定性受损以及代谢改变。整合分析结果显示，VCL参与炎症反应、细胞黏附与细胞外渗等病理生理过程。验证队列（validation cohort）证实，VCL与细胞间黏附分子1（ICAM1）可作为奥密克戎感染的关联生物标志物。小鼠模型（mouse model）实验不仅验证了上述发现，还表明靶向VCL具有治疗潜力。与既往基因组研究聚焦新冠感染中的宿主免疫与感染易感性不同，本研究揭示了奥密克戎变异株通过VCL通路诱导的进行性生理损伤。本研究阐明的核心致病分子机制，可为针对新兴SARS-CoV-2变异株的治疗手段开发提供战略方向，同时强调了持续调整防控策略以应对病毒挑战的必要性。