作者
Andrew Kwok,Alice Allcock,Ricardo C. Ferreira,Eddie Cano-Gamez,Madeleine Smee,Katie L Burnham,Yasemin-Xiomara Zurke,Alex Novak,Melanie Darwent,Tanya Baron,Charlotte Brown,Sally Beer,Alexis Espinosa,Tine Panduro,Dominique Georgiou,Jose Martinez,Hannah Thraves,Elena Perez,Rocío Fernández,Alberto Sobrino,Verónica Sánchez,Rufino Magallano,Karen Dineen,Jean Wilson,Stuart McKechnie,Alexander J. Mentzer,Claudia Monaco,Irina A. Udalova,C. J. Hinds,John A. Todd,Emma E Davenport,Julian C. Knight
摘要
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.