Liu Yakun, Garron Tania M, Chang Qing, Su Zhengchen, Zhou Changcheng, Qiu Yuan, Gong Eric C, Zheng Junying, Yin Y Whitney, Ksiazek Thomas, Brasel Trevor, Jin Yang, Boor Paul, Comer Jason E, Gong Bin
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Pathogens. 2021 Apr 23;10(5):509. doi: 10.3390/pathogens10050509.
The SARS-CoV-2 pandemic has inspired renewed interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS) following infection. However, the pathogenesis of ARDS following SRAS-CoV-2 infection remains largely unknown. In the present study, we examined apoptosis in postmortem lung sections from COVID-19 patients and in lung tissues from a non-human primate model of SARS-CoV-2 infection, in a cell-type manner, including type 1 and 2 alveolar cells and vascular endothelial cells (ECs), macrophages, and T cells. Multiple-target immunofluorescence assays and Western blotting suggest both intrinsic and extrinsic apoptotic pathways are activated during SARS-CoV-2 infection. Furthermore, we observed that SARS-CoV-2 fails to induce apoptosis in human bronchial epithelial cells (i.e., BEAS2B cells) and primary human umbilical vein endothelial cells (HUVECs), which are refractory to SARS-CoV-2 infection. However, infection of co-cultured Vero cells and HUVECs or Vero cells and BEAS2B cells with SARS-CoV-2 induced apoptosis in both Vero cells and HUVECs/BEAS2B cells but did not alter the permissiveness of HUVECs or BEAS2B cells to the virus. Post-exposure treatment of the co-culture of Vero cells and HUVECs with a novel non-cyclic nucleotide small molecule EPAC1-specific activator reduced apoptosis in HUVECs. These findings may help to delineate a novel insight into the pathogenesis of ARDS following SARS-CoV-2 infection.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行激发了人们对了解感染后急性呼吸窘迫综合征（ARDS）基本病理学的新兴趣。然而，SARS-CoV-2感染后ARDS的发病机制仍 largely未知。在本研究中，我们以细胞类型的方式，包括1型和2型肺泡细胞、血管内皮细胞（ECs）、巨噬细胞和T细胞，检查了COVID-19患者尸检肺组织切片以及SARS-CoV-2感染的非人灵长类动物模型肺组织中的细胞凋亡情况。多靶点免疫荧光分析和蛋白质印迹表明，SARS-CoV-2感染期间内在和外在凋亡途径均被激活。此外，我们观察到SARS-CoV-2无法在对SARS-CoV-2感染具有抗性的人支气管上皮细胞（即BEAS2B细胞）和人脐静脉内皮细胞（HUVECs）中诱导细胞凋亡。然而，用SARS-CoV-2感染共培养的Vero细胞和HUVECs或Vero细胞和BEAS2B细胞，可在Vero细胞和HUVECs/BEAS2B细胞中诱导细胞凋亡，但不会改变HUVECs或BEAS2B细胞对病毒的易感性。用一种新型非环核苷酸小分子EPAC1特异性激活剂对Vero细胞和HUVECs的共培养物进行暴露后处理，可减少HUVECs中的细胞凋亡。这些发现可能有助于阐明对SARS-CoV-2感染后ARDS发病机制的新见解。
