Gultom Mitra, Lin Lin, Brandt Camilla Blunk, Milusev Anastasia, Despont Alain, Shaw Jane, Döring Yvonne, Luo Yonglun, Rieben Robert
Department for Biomedical Research, University of Bern, Bern, Switzerland.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Inflammation. 2024 Dec 31. doi: 10.1007/s10753-024-02208-x.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with systemic inflammation and vascular injury, which contribute to the development of acute respiratory syndrome (ARDS) and the mortality of COVID-19 infection. Moreover, multiorgan complications due to persistent endothelial dysfunction have been suspected as the cause of post-acute sequelae of SARS-CoV-2 infection. Therefore, elucidation of the vascular inflammatory effect of SARS-CoV-2 will increase our understanding of how endothelial cells (ECs) contribute to the short- and long-term consequences of SARS-CoV-2 infection. Here, we investigated the interaction of SARS-CoV-2 spike protein with human ECs from aortic (HAoEC) and pulmonary microvascular (HPMC) origins, cultured under physiological flow conditions. We showed that the SARS-CoV-2 spike protein triggers prolonged expression of cell adhesion markers in both ECs, similar to the effect of TNF-α. SARS-CoV-2 spike treatment also led to the release of various cytokines and chemokines observed in severe COVID-19 patients. Moreover, increased binding of leucocytes to the endothelial surface and a procoagulant state of the endothelium were observed. Transcriptomic profiles of SARS-CoV-2 spike-activated HPMC and HAoEC showed prolonged upregulation of genes and pathways associated with responses to virus, cytokine-mediated signaling, pattern recognition, as well as complement and coagulation pathways. Our findings support experimental and clinical observations of the vascular consequences of SARS-CoV-2 infection and highlight the importance of EC protection as one of the strategies to mitigate the severe effects as well as the possible post-acute complications of COVID-19 disease.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染与全身炎症和血管损伤有关，这有助于急性呼吸综合征（ARDS）的发展以及COVID-19感染的死亡率。此外，由于持续性内皮功能障碍导致的多器官并发症被怀疑是SARS-CoV-2感染后急性后遗症的原因。因此，阐明SARS-CoV-2的血管炎症作用将增加我们对内皮细胞（ECs）如何导致SARS-CoV-2感染的短期和长期后果的理解。在这里，我们研究了SARS-CoV-2刺突蛋白与来自主动脉（HAoEC）和肺微血管（HPMC）的人ECs在生理流动条件下培养时的相互作用。我们发现，SARS-CoV-2刺突蛋白在两种ECs中均触发细胞粘附标志物的延长表达，类似于TNF-α的作用。SARS-CoV-2刺突蛋白处理还导致了在重症COVID-19患者中观察到的各种细胞因子和趋化因子的释放。此外，观察到白细胞与内皮表面的结合增加以及内皮的促凝状态。SARS-CoV-2刺突蛋白激活的HPMC和HAoEC的转录组谱显示，与病毒反应、细胞因子介导的信号传导、模式识别以及补体和凝血途径相关的基因和途径持续上调。我们的研究结果支持了SARS-CoV-2感染血管后果的实验和临床观察，并强调了保护ECs作为减轻COVID-19疾病严重影响以及可能的急性后并发症的策略之一的重要性。
