SARS-CoV-2 infects and induces cytotoxic effacts in human cardiomyocytes
SARS-CoV-2 infects and induces cytotoxic effacts in human cardiomyocytes
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DOI：
10.1093/cvr/cvaa267
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发表时间：
2020-12-01
影响因子：
10.8
通讯作者：
Dimmeler, Stefanie
中科院分区：
文献类型：
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作者：
Bojkova, Denisa;Wagner, Julian U. G.;Dimmeler, Stefanie
2019冠状病毒病是由严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）引起的，已成为全球大流行。SARS-CoV-2感染可导致与更高死亡风险相关的心脏损伤标志物升高。目前尚不清楚心脏损伤是由心肌细胞直接感染引起的，还是主要继发于肺损伤和炎症。在这里，我们研究心肌细胞是否允许SARS-CoV-2感染。方法和结果检测细胞内双链病毒RNA和病毒刺突糖蛋白表达，证实两株SARS-CoV-2感染人诱导多能干细胞衍生心肌细胞。在感染心肌细胞的上清液中检测到病毒RNA浓度增加，这诱导了Caco-2细胞系的感染，记录了生产性感染。SARS-CoV-2感染及其诱导的细胞毒性和促凋亡作用可消除心肌细胞跳动。RNA测序证实了对病毒感染的转录应答，与病毒应答、干扰素信号、细胞凋亡和活性氧应激相关的通路相关的基因上调证实了这一点。在三维心肌组织模型中证实了SARS-CoV-2感染和心脏毒性。重要的是，在感染SARS-CoV-2后的活体心脏切片中检测到病毒刺突蛋白和病毒颗粒。在2019冠状病毒病患者的心肌细胞中进一步观察到冠状病毒颗粒。诱导多能干细胞来源的心肌细胞感染依赖于组织蛋白酶和血管紧张素转换酶2，并被瑞德西韦阻断。结论SARS-CoV-2以血管紧张素转换酶2和组织蛋白酶依赖的方式感染体外心肌细胞。抗病毒药物瑞德西韦可抑制心肌细胞感染SARS-CoV-2。
Aims Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to Lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection.Methods and results Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir.Conclusion This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.[GRAPHICS].