Lai Cong, Lu Su, Yang Yilin, You Xiaoyu, Xu Feixiang, Deng Xinran, Lan Lulu, Guo Yuesheng, Kuang Zhongshu, Luo Yue, Yuan Li, Meng Lu, Wu Xueling, Song Zhenju, Jiang Ning
Department of Emergency Medicine, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Institute of Infection and Health, Fudan University, Shanghai, China.
J Med Virol. 2025 Apr;97(4):e70335. doi: 10.1002/jmv.70335.
The objective of this study was to better understand immune failure mechanisms during severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 infection, which are critical for developing targeted vaccines and effective treatments. We collected 34 cases representing different disease severities and performed high-quality single-cell TCR/BCR sequencing to analyze the peripheral immune cell profiles. Additionally, we assessed antibody-neutralizing activity through in vitro experiments. Our integrated multiomics analysis uncovers a profound immune paradox in severe COVID-19: hyperinflammation coexists with immunosuppression, driven by distinct yet interconnected dysregulatory mechanisms. Severe patients develop robust humoral immunity, evidenced by clonally expanded plasma cells producing neutralizing antibodies (e.g., IGHG1-dominated responses) and antigen-specific T cell activation. However, these protective responses are counteracted by myeloid-driven immunosuppression, particularly CD14+ HMGB2+ monocytes exhibiting metabolic reprogramming and HLA-DR downregulation, coupled with progressive T cell exhaustion characterized by IFN-γ/TNF-α hyperactivation and impaired antigen presentation. Importantly, prolonged viral persistence in severe cases arises from a failure to coordinate humoral and cellular immunity-antibody-mediated neutralization cannot compensate for defective cytotoxic T cell function and monocyte-mediated immune suppression. These findings highlight the necessity for therapeutic strategies that simultaneously enhance antibody effector functions (e.g., Fc optimization), restore exhausted T cells, and reverse myeloid suppression. They also highlight the importance of vaccines designed to elicit balanced B cell memory and durable T cell responses, which are critical to preventing severe disease progression. By addressing the dual challenges of hyperinflammation and immunosuppression, such approaches could restore immune coordination and improve outcomes in severe COVID-19.
本研究的目的是更好地了解严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染期间的免疫衰竭机制，这对于开发靶向疫苗和有效治疗方法至关重要。我们收集了34例代表不同疾病严重程度的病例，并进行了高质量的单细胞TCR/BCR测序，以分析外周免疫细胞谱。此外，我们通过体外实验评估了抗体中和活性。我们的综合多组学分析揭示了重症COVID-19中一个深刻的免疫悖论：炎症反应过度与免疫抑制并存，由不同但相互关联的失调机制驱动。重症患者产生了强大的体液免疫，表现为产生中和抗体的克隆性扩增浆细胞（例如，以IGHG1为主导的反应）和抗原特异性T细胞活化。然而，这些保护性反应被髓系驱动的免疫抑制所抵消，特别是CD14+HMGB2+单核细胞表现出代谢重编程和HLA-DR下调，同时伴有以IFN-γ/TNF-α过度活化和抗原呈递受损为特征的渐进性T细胞耗竭。重要的是，重症病例中病毒的持续存在是由于未能协调体液免疫和细胞免疫——抗体介导的中和作用无法弥补细胞毒性T细胞功能缺陷和单核细胞介导的免疫抑制。这些发现凸显了同时增强抗体效应功能（例如，Fc优化）、恢复耗竭的T细胞和逆转髓系抑制的治疗策略的必要性。它们还强调了设计能够引发平衡的B细胞记忆和持久的T细胞反应的疫苗的重要性，这对于预防严重疾病进展至关重要。通过应对炎症反应过度和免疫抑制这两个双重挑战，此类方法可以恢复免疫协调并改善重症COVID-19的治疗结果。
