Genome-wide DNA methylation profiling of peripheral blood reveals an epigenetic signature associated with severe COVID-19
Genome-wide DNA methylation profiling of peripheral blood reveals an epigenetic signature associated with severe COVID-19
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DOI：
10.1002/jlb.5hi0720-466r
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发表时间：
2021-01-19
影响因子：
5.5
通讯作者：
Ndhlovu, Lishomwa C.
中科院分区：
文献类型：
--
作者：
Corley, Michael J.;Pang, Alina P. S.;Ndhlovu, Lishomwa C.
由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起的全球大流行是一种高致病性RNA病毒，在人类中引起2019冠状病毒病（COVID-19）。尽管大多数COVID-19患者病情较轻，可能没有症状，但有些人会发展为重症肺炎、急性呼吸窘迫综合征、多器官衰竭和死亡。RNA病毒如SARS-CoV-2能够劫持宿主免疫细胞的表观遗传景观，以逃避抗病毒防御。然而，在我们对与严重SARS-CoV-2感染病理学相关的免疫细胞表观遗传变化的理解方面仍存在相当大的差距。在这里，我们检测了9例确诊为SARS-CoV-2血浆病毒血症的晚期危重COVID-19患者外周血单核细胞的全基因组DNA甲基化（DNAm）谱，并与未感染的住院流感患者、未经治疗的原发性HIV感染者和轻度/中度COVID-19 HIV合并感染者进行了比较。细胞类型去卷积分析证实了严重COVID-19中的淋巴细胞减少症，并显示了高百分比的估计中性粒细胞，表明与粒细胞生成相关的DNAm扰动。我们观察到严重COVID-19的独特DNAm特征，其特征是IFN相关基因的高甲基化和炎症基因的低甲基化，这加强了严重COVID-19感染模型和单细胞转录研究中的观察结果。根据GrimAge，表观遗传时钟分析显示，严重的COVID-19与DNA年龄增加和死亡风险升高相关，进一步验证了表观遗传时钟作为疾病和死亡风险的预测因子。我们的表观遗传学结果揭示了血液中严重COVID-19的发现DNAm特征，可能有助于证实临床评估，告知致病机制，并揭示针对SARS-CoV-2的新治疗靶点。
The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID-19) in humans. Although most patients with COVID-19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi-organ failure, and death. RNA viruses such as SARS-CoV-2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS-CoV-2 infection pathology. Here, we examined genome-wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally-ill, critical COVID-19 patients with confirmed SARS-CoV-2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID-19 HIV coinfected individuals. Cell-type deconvolution analyses confirmed lymphopenia in severe COVID-19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID-19 characterized by hypermethylation of IFN-related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single-cell transcriptional studies of severe COVID-19. Epigenetic clock analyses revealed severe COVID-19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID-19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS-CoV-2.