Xiao Kun, Cao Yan, Yan Peng, Hu Ye, Luu Laurence Don Wai, Pan Pan, Gu Hongjun, Duan Zhimei, Wang Jiaxing, Chen Wei, Chen Xuxin, Zhang Jianhong, Zou Wailong, Sun Peipei, Chen Liang, Chen Jichao, Xiang Pingchao, Xie Lixin, Wang Yi
College of Pulmonary & Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China.
Department of Pulmonary and Critical Care Medicine, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, People's Republic of China.
Am J Respir Crit Care Med. 2025 Dec;211(12):2363-2381. doi: 10.1164/rccm.202501-0217OC.
Bacterial pneumonia poses a substantial global health burden; yet, the immunological mechanisms driving disease pathogenesis and resolution are incompletely understood. We generated a large-scale single-cell transcriptomic atlas of peripheral blood immune cells from 100 individuals: 39 with severe bacterial pneumonia, 31 with mild disease, and 30 healthy control subjects. Integrating single-cell RNA sequencing with clinical and molecular data revealed profound remodeling of the peripheral immune landscape across disease severities. Severe pneumonia was characterized by lymphopenia and monocytosis, accompanied by distinct shifts in T cell, B cell, and myeloid cell subset composition. Classical monocytes emerged as central orchestrators of the cytokine storm observed in severe cases, displaying elevated expression of proinflammatory genes (e.g., ) and enhanced TLR4-MYD88 signaling. Exhaustion of innate-like CD8 T cells, marked by upregulation of canonical inhibitory receptors, was a hallmark of severe disease. In contrast, mild pneumonia exhibited robust CD8 T effector and helper memory cell activation, together with effective humoral immunity, evidenced by plasma cell expansion and coordinated T follicular helper cell-B cell interactions. B cells in mild cases showed enhanced antigen recognition, BCR signaling, and costimulatory gene expression, whereas those in severe cases displayed signs of dysfunction. Myeloid cell alterations in severe pneumonia included increased monocytic myeloid-derived suppressor cells and nonclassical monocytes, contributing to immunosuppression and complement overactivation, respectively. This high-resolution atlas of peripheral immune responses in bacterial pneumonia identifies key cellular and molecular drivers of disease severity, providing potential therapeutic targets for immunomodulation and improved outcomes.
细菌性肺炎给全球健康带来了沉重负担；然而，驱动疾病发病机制和转归的免疫机制尚未完全明确。我们生成了100名个体外周血免疫细胞的大规模单细胞转录组图谱：39例重症细菌性肺炎患者、31例轻症患者和30名健康对照者。将单细胞RNA测序与临床和分子数据相结合，揭示了不同疾病严重程度外周免疫格局的深刻重塑。重症肺炎的特征是淋巴细胞减少和单核细胞增多，同时T细胞、B细胞和髓样细胞亚群组成发生明显变化。经典单核细胞成为重症病例中观察到的细胞因子风暴的核心调控者，表现为促炎基因（如 ）表达升高以及TLR4-MYD88信号增强。以经典抑制性受体上调为特征的先天性样CD8 T细胞耗竭是重症疾病的一个标志。相比之下，轻症肺炎表现出强大的CD8 T效应细胞和辅助记忆细胞激活，以及有效的体液免疫，表现为浆细胞扩增和T滤泡辅助细胞与B细胞的协同相互作用。轻症病例中的B细胞显示出增强的抗原识别、BCR信号传导和共刺激基因表达，而重症病例中的B细胞则表现出功能障碍的迹象。重症肺炎中的髓样细胞改变包括单核细胞来源的髓样抑制细胞和非经典单核细胞增加，分别导致免疫抑制和补体过度激活。这一细菌性肺炎外周免疫反应的高分辨率图谱确定了疾病严重程度的关键细胞和分子驱动因素，为免疫调节和改善预后提供了潜在的治疗靶点。
