Ben-Ami Roni, Loyfer Netanel, Cohen Eden, Fialkoff Gavriel, Sharkia Israa, Piyanzin Sheina, Bogot Naama, Kochan Danit, Kalak George, Jarjoui Amir, Chen-Shuali Chen, Azulai Hava, Barhoum Hezi, Arish Nissim, Greenberger Moshe M, Velleman David, Kurd Ramzi, Ben-Chetrit Eli, Bohm Davina, Wolak Talya, Quteineh Ahmad, Cann Gordon, Glaser Benjamin, Friedman Nir, Kaplan Tommy, Shemer Ruth, Rokach Ariel, Dor Yuval
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
School of Computer Science, Hebrew University of Jerusalem, Jerusalem, Israel.
Life Sci Alliance. 2025 Aug 5;8(10). doi: 10.26508/lsa.202503417. Print 2025 Oct.
Understanding the full spectrum of tissues affected by SARS-CoV-2 is crucial for deciphering the heterogeneous clinical course of COVID-19. We analyzed DNA methylation and histone modifications in circulating chromatin to assess cell type-specific turnover in patients ranging from asymptomatic to severe cases, in relation to clinical outcomes. Severe COVID-19 was marked by a massive elevation of circulating cell-free DNA (cfDNA) from lung epithelium, cardiomyocytes, vascular endothelium, and erythroblasts, indicating increased cell death or turnover. The immune response was reflected by elevated B-cell and monocyte/macrophage cfDNA and an interferon response before cfDNA release. Strikingly, monocyte/macrophage cfDNA (but not monocyte counts), as well as lung epithelial and endothelial cfDNA, predicted clinical deterioration and duration of hospitalization. Asymptomatic patients had elevated immune cfDNA but no evidence of pulmonary or cardiac damage. Surprisingly, these patients showed elevated endothelial and erythroblast cfDNA, suggesting subclinical vascular and erythrocyte turnover are universal features of COVID-19, independent of disease severity. Epigenetic liquid biopsies provide a noninvasive means of monitoring COVID-19 patients and reveal subclinical vascular damage and red blood cell turnover.
了解受严重急性呼吸综合征冠状病毒2（SARS-CoV-2）影响的全谱组织对于解读2019冠状病毒病（COVID-19）的异质性临床病程至关重要。我们分析了循环染色质中的DNA甲基化和组蛋白修饰，以评估从无症状到重症病例患者的细胞类型特异性更新情况，并将其与临床结果相关联。重症COVID-19的特征是来自肺上皮细胞、心肌细胞、血管内皮细胞和成红细胞的循环游离DNA（cfDNA）大量升高，表明细胞死亡或更新增加。免疫反应通过B细胞和单核细胞/巨噬细胞cfDNA升高以及cfDNA释放前的干扰素反应得以体现。引人注目的是，单核细胞/巨噬细胞cfDNA（而非单核细胞计数）以及肺上皮和内皮cfDNA可预测临床恶化和住院时间。无症状患者的免疫cfDNA升高，但无肺部或心脏损伤的证据。令人惊讶的是，这些患者的内皮和成红细胞cfDNA升高，表明亚临床血管和红细胞更新是COVID-19的普遍特征，与疾病严重程度无关。表观遗传液体活检提供了一种监测COVID-19患者的非侵入性方法，并揭示了亚临床血管损伤和红细胞更新情况。
