Maguire Cole, Chen Jing, Rouphael Nadine, Pickering Harry, Phan Hoang Van, Glascock Abigail, Chu Victoria, Dandekar Ravi, Corry David, Kheradmand Farrah, Baden Lindsey R, Selaky Rafick, McComsey Grace A, Haddad Elias K, Cairns Charles B, Pulendran Bali, Fernandez-Sesma Ana, Simon Viviana, Metcalf Jordan P, Higuita Nelson I Agudelo, Messer William B, David Mark M, Nadeau Kari C, Kraft Monica, Bime Chris, Schaenman Joanna, Erle David, Calfee Carolyn S, Atkinson Mark A, Brackenridge Scott C, Ehrlich Lauren I R, Montgomery Ruth R, Shaw Albert C, Hough Catherine L, Geng Linda N, Hafler David A, Augustine Alison D, Becker Patrice M, Peters Bjoern, Ozonoff Al, Kim-Schulze Seunghee Hee, Krammer Florian, Bosinger Steve, Eckalbar Walter, Altman Matthew C, Wilson Michael, Guan Leying, Kleinstein Steven H, Smolen Kinga K, Reed Elaine F, Levy Ofer, Maecker Holden, Hunt Peter, Steen Hanno, Diray-Arce Joann, Langelier Charles R, Melamed Esther
The University of Texas at Austin, Austin, TX 78712, USA.
Clinical and Data Coordinating Center (CDCC) Precision Vaccines Program, Boston Children's Hospital, Boston, MA 02115, USA.
bioRxiv. 2024 Nov 16:2024.11.14.622799. doi: 10.1101/2024.11.14.622799.
Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS-CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of , , and families during acute stage of COVID-19 (0-40 days post-hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID-19 and PASC.
慢性病毒感染在人类中普遍存在，个体携带多种潜伏病毒，这些病毒可在急性疾病期间重新激活。最近的研究表明，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染可导致潜伏病毒如爱泼斯坦-巴尔病毒（EBV）和巨细胞病毒（CMV）重新激活，然而，新冠病毒病（COVID-19）中病毒重新激活的程度和影响及其对宿主免疫系统的作用仍未完全了解。在此，我们对1154例住院COVID-19患者中所有已知慢性感染病毒的病毒重新激活进行了全面的多组学分析，这些患者来自COVID-19队列免疫表型评估（IMPACC）研究，并进行了为期12个月的前瞻性随访。我们发现，在COVID-19急性期（住院后0至40天）， 、 和 家族有显著的重新激活，每种病毒都表现出独特的时间动态。我们还表明，病毒重新激活与COVID-19的严重程度、人口统计学特征和临床结局（包括死亡率）相关。细胞因子谱分析、细胞免疫表型分析、代谢组学、转录组学和蛋白质组学的整合显示了病毒特异性的宿主反应，包括促炎细胞因子（如白细胞介素-6、CXC趋化因子配体10和肿瘤坏死因子）升高、活化的CD4+和CD8+T细胞增加以及细胞复制基因上调，且与COVID-19严重程度和SARS-CoV-2病毒载量无关。值得注意的是，恢复期（住院后≥3个月）持续的 重新激活与COVID-19急性后遗症（PASC）症状相关，尤其是身体功能和疲劳。我们的研究结果突出了慢性病毒重新激活在急性COVID-19期间对宿主反应和临床结局以及长期PASC后遗症的显著普遍性和潜在影响。我们的数据提供了病毒重新激活的新型免疫、转录组和代谢组生物标志物，可为预测、预防或治疗急性COVID-19和PASC的新方法提供信息。
