Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19-associated Coagulopathies.
Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19-associated Coagulopathies.
复制标题
肺上皮细胞转录调节作为COVID-19相关凝血病的一个因素。
DOI：
10.1165/rcmb.2020-0453oc
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发表时间：
2021-06
影响因子：
6.4
通讯作者：
Jamieson AM
中科院分区：
文献类型：
--
作者：
FitzGerald ES;Chen Y;Fitzgerald KA;Jamieson AM
严重急性呼吸综合征冠状病毒2(SARS-CoV-2)已迅速成为一种全球大流行。除了冠状病毒病(新冠肺炎)的急性肺部症状(与SARS-CoV-2感染有关的疾病)外，肺部和远端凝血疾病还导致许多患者的发病率和死亡率。目前，新冠肺炎相关凝血疾病的分子发病机制尚不清楚。确定SARS-CoV-2如何驱动凝血的分子基础对于降低新冠肺炎患者和康复患者的短期和长期血栓形成风险至关重要。我们的目标是在SARS-CoV-2感染过程中，对体外感染的原代呼吸道上皮细胞、患者来源的支气管肺泡灌洗细胞和循环免疫细胞进行凝血聚焦转录组分析。我们的目标是确定转录介导的信号网络驱动与新冠肺炎相关的凝血疾病。我们分析了最近发表的SARS-CoV-2感染的实验和临床来源的批量或单细胞RNA测序数据集，以确定凝血转录调节的变化。我们还证实了一个关键的凝血调节因子的转录表达是在蛋白质水平上重现的。我们特别侧重于肺组织表达的调节外源性凝血级联和纤溶酶原激活系统的基因的分析。体外感染正常人支气管上皮细胞和患者来源的肺泡灌洗液标本的转录数据分析表明，SARS-CoV-2感染诱导了外源性凝血级联反应，抑制了纤溶酶原激活系统。我们还在原代培养的人肺上皮细胞上进行了SARS-CoV-2感染实验，以证实外源性凝血级联主调节因子组织因子在蛋白质水平上的转录上调。此外，感染A型流感病毒的正常人支气管上皮细胞并不像SARS-CoV-2那样驱动凝血的关键调节因子。此外，在SARS-CoV-2感染过程中，外周血单个核细胞没有差异表达调控外源性凝血级联或纤溶酶原激活系统的基因，这表明它们不是通过这些途径直接诱导凝血障碍。在SARS-CoV-2感染的上皮细胞中，外源性凝血级联的过度激活和纤溶酶原激活系统的抑制可能导致肺和远端器官系统的多种凝血疾病。了解宿主如何在SARS-CoV-2感染中驱动这种转录变化，可能有助于设计针对宿主的治疗策略，以治疗新冠肺炎和其他导致高凝的冠状病毒。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of coronavirus disease (COVID-19) (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19–associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short- and long-term thrombotic risks of sick and recovered patients with COVID-19. We aimed to perform coagulation-focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient-derived bronchial alveolar lavage cells, and circulating immune cells during SARS-CoV-2 infection. Our objective was to identify transcription-mediated signaling networks driving coagulopathies associated with COVID-19. We analyzed recently published experimentally and clinically derived bulk or single-cell RNA sequencing datasets of SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the protein level. We specifically focused our analysis on lung tissue–expressed genes regulating the extrinsic coagulation cascade and the plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial cells and patient-derived bronchial alveolar lavage samples revealed that SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the plasminogen activation system. We also performed in vitro SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of tissue factor, the extrinsic coagulation cascade master regulator, manifested at the protein level. Furthermore, infection of normal human bronchial epithelial cells with influenza A virus did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. In addition, peripheral blood mononuclear cells did not differentially express genes regulating the extrinsic coagulation cascade or plasminogen activation system during SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyperactivation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2–infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat COVID-19 and other coronaviruses inducing hypercoagulation.