Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Nat Immunol. 2023 May;24(5):767-779. doi: 10.1038/s41590-023-01490-5. Epub 2023 Apr 24.
Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b sepsis neutrophils inhibited proliferation and activation of CD4 T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2 immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.
脓毒症是由感染后宿主反应失调引起的，其机制尚不完全清楚，可导致危及生命的器官功能障碍。在这里，我们发现中性粒细胞和应急性粒细胞生成在脓毒症中引发了适应性不良的反应。我们生成了脓毒症免疫反应的全血单细胞多组学图谱（272993 个细胞，n=39 人），鉴定出了具有免疫抑制功能的成熟和不成熟中性粒细胞群体。在共培养实验中，CD66b 阳性脓毒症中性粒细胞抑制 CD4 T 细胞的增殖和激活。对循环造血干细胞和祖细胞（HSPCs）（29366 个细胞，n=27）的单细胞多组学图谱分析表明，脓毒症患者的粒细胞生成发生改变。这些特征在预后不良的患者亚群中更为丰富，同时还存在脓毒症特异性反应特征，即 IL1R2 阳性幼稚中性粒细胞频率升高、HSPCs 中应急性粒细胞生成的表观遗传和转录组学特征以及不同感染病因和综合征中 STAT3 介导的基因调控。我们的研究结果为严重感染的治疗靶点和分层医学提供了潜在机会。
