Li Jingwei, Liang Shufan, Li Yalun, Wu Jiayang, Li Changshu, Gan Jiadi, Li Weimin, Wang Chengdi
Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
Respir Res. 2026 Jan 15;27(1):53. doi: 10.1186/s12931-025-03465-6.
Severe respiratory infections have imposed an immense burden on healthcare worldwide, which could lead to fatal outcomes. The dysfunctional immune response impacts disease severity of respiratory infections, yet its underlying mechanisms remain largely obscure.
We explored the immunologic response underpinning severe respiratory viral infections by performing single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from 17 patients with coronavirus disease 2019 (COVID-19), including moderate, severe, critical, and convalescent cases. Furthermore, we analyzed the host responses following low- or high-dose vaccination with recombinant protein.
We constructed an immunocyte landscape with 299,527 PBMCs. The significant dysregulation of immune homeostasis in severe respiratory viral infections was characterized by an increased ratio of CD14 monocytes and exhausted CD8 T cells, and reduced Tregs, memory T cells and cDC2 cells. Notably, highly inflamed CD14 monocytes overexpressing interleukin (IL)-related genes emerged as central contributor of inflammatory storms in critical patients. Enhanced inflammatory response in exhausted CD8 T cells, FOS/JUN overexpression in Tregs and Th17 cells, as well as suppressed antigen presentation activity in cDC2 cells were also remarkable features of severe and critical cases. Moreover, the high-dose vaccination with recombinant protein inhibited the inflammatory response of CD14 monocytes, while enriched the memory T/NK cells to boost protective immunity. In mechanism, activated IL-6-JAK-STAT in CD14 monocytes and T cells, coupled with impaired interferon (IFN)-α pathway, could drive excessive inflammatory response.
Our study creates a high-resolution transcriptomic atlas that uncovers distinct immune signatures across the disease severity of respiratory infections, which provides valuable resource for mechanistic exploration and therapeutic strategies development. Furthermore, we demonstrate that high-dose recombinant protein vaccines might mitigate the severity of illness.
This study was prospectively registered at ChiCTR (Registration number: ChiCTR2300067787).
严重呼吸道感染给全球医疗保健带来了巨大负担，可能导致致命后果。免疫反应功能失调会影响呼吸道感染的疾病严重程度，但其潜在机制在很大程度上仍不清楚。
我们通过对17例2019冠状病毒病（COVID-19）患者的外周血单个核细胞（PBMC）进行单细胞转录组分析，包括中度、重度、危重症和康复期病例，探索了严重呼吸道病毒感染背后的免疫反应。此外，我们分析了重组蛋白低剂量或高剂量疫苗接种后的宿主反应。
我们构建了包含299,527个PBMC的免疫细胞图谱。严重呼吸道病毒感染中免疫稳态的显著失调表现为CD14单核细胞和耗竭性CD8 T细胞比例增加，以及调节性T细胞、记忆性T细胞和cDC2细胞减少。值得注意的是，过度表达白细胞介素（IL）相关基因的高度炎症性CD14单核细胞成为危重症患者炎症风暴的主要促成因素。耗竭性CD8 T细胞中增强的炎症反应、调节性T细胞和Th17细胞中FOS/JUN的过表达，以及cDC2细胞中抗原呈递活性的抑制也是重度和危重症病例的显著特征。此外，重组蛋白高剂量疫苗接种抑制了CD14单核细胞的炎症反应，同时富集了记忆性T/NK细胞以增强保护性免疫。在机制上，CD14单核细胞和T细胞中激活的IL-6-JAK-STAT，以及受损的干扰素（IFN）-α途径，可能驱动过度的炎症反应。
我们的研究创建了一个高分辨率转录组图谱，揭示了呼吸道感染不同疾病严重程度下独特的免疫特征，为机制探索和治疗策略开发提供了有价值的资源。此外，我们证明高剂量重组蛋白疫苗可能减轻疾病严重程度。
本研究已在中国临床试验注册中心前瞻性注册（注册号：ChiCTR2300067787）。
