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Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart
Cardiovascular Research ( IF 10.8 ) Pub Date : 2021-10-13 , DOI: 10.1093/cvr/cvab322
Hanna Bräuninger 1, 2 , Bastian Stoffers 1, 2 , Antonia D E Fitzek 3 , Kira Meißner 3 , Ganna Aleshcheva 4 , Michaela Schweizer 5 , Jessica Weimann 1 , Björn Rotter 6 , Svenja Warnke 1 , Carolin Edler 3 , Fabian Braun 7 , Kevin Roedl 8 , Katharina Scherschel 1, 9, 10 , Felicitas Escher 4, 11, 12 , Stefan Kluge 8 , Tobias B Huber 7 , Benjamin Ondruschka 3 , Heinz-Peter Schultheiss 4 , Paulus Kirchhof 1, 2, 13 , Stefan Blankenberg 1, 2 , Klaus Püschel 3 , Dirk Westermann 1, 2 , Diana Lindner 1, 2
Affiliation  

Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. Methods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value <0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The Gene Ontology (GO) term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response. Conclusion This study reveals that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.

中文翻译:

心脏 SARS-CoV-2 感染与心脏内的促炎转录组改变有关

目的 心脏参与 COVID-19 与不良结果相关。然而,尚不清楚细胞特异性后果是否与心脏 SARS-CoV-2 感染有关。因此,我们在连续尸检病例中利用原位杂交、免疫组织化学和 RNA 测序研究了心脏组织,以量化病毒载量并表征 COVID-19 中的心脏受累情况。方法和结果 本研究纳入 95 例 SARS-CoV-2 阳性尸检病例。在 41/95 的死者 (43%) 中检测到心脏组织中的相关 SARS-CoV-2 病毒载量。对 cDNA 末端 (MACE)-RNA 测序进行了大量分析,以识别由心脏感染引起的分子病理机制。基于单细胞数据集“心脏细胞图谱”生成签名矩阵,并用于 MACE-RNA 测序数据的数字细胞计数。因此,估计免疫细胞分数并显示在有和没有心脏感染的情况下免疫细胞数量没有差异。该结果通过定量免疫组织学诊断得到证实。MACE-RNA 测序揭示了 19 个差异表达基因 (DEG),其 q 值<0.05(例如向上:IFI44L、IFT3、TRIM25;向下:NPPB、MB、MYPN)。上调的 DEG 与干扰素途径相关,主要来源于内皮细胞。相反,下调的 DEG 主要来自心肌细胞。免疫荧光染色显示内皮标记 ICAM1 阳性细胞中的病毒蛋白,但在心肌细胞中很少见。基因本体论 (GO) 术语分析显示,下调的 GO 术语与心肌细胞结构有关,而上调的 GO 术语与抗病毒免疫反应有关。结论 本研究表明,心脏感染引起的转录组改变主要与免疫反应和心肌细胞的破坏有关。虽然内皮细胞主要被病毒靶向,但我们建议通过旁分泌效应破坏心肌细胞。在 SARS-CoV-2 感染的心脏组织中检测到促炎基因表达增加,但未观察到与 SARS-CoV-2 相关的免疫细胞浸润增加。结论 本研究表明,心脏感染引起的转录组改变主要与免疫反应和心肌细胞的破坏有关。虽然内皮细胞主要被病毒靶向,但我们建议通过旁分泌效应破坏心肌细胞。在 SARS-CoV-2 感染的心脏组织中检测到促炎基因表达增加,但未观察到与 SARS-CoV-2 相关的免疫细胞浸润增加。结论 本研究表明,心脏感染引起的转录组改变主要与免疫反应和心肌细胞的破坏有关。虽然内皮细胞主要被病毒靶向,但我们建议通过旁分泌效应破坏心肌细胞。在 SARS-CoV-2 感染的心脏组织中检测到促炎基因表达增加,但未观察到与 SARS-CoV-2 相关的免疫细胞浸润增加。
更新日期:2021-10-13
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