An immune-cell signature of bacterial sepsis

• Published in: Nature medicine Vol. 26; no. 3; pp. 333 - 340
• Main Authors: Reyes, Miguel, Filbin, Michael R., Bhattacharyya, Roby P., Billman, Kianna, Eisenhaure, Thomas, Hung, Deborah T., Levy, Bruce D., Baron, Rebecca M., Blainey, Paul C., Goldberg, Marcia B., Hacohen, Nir
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2020; Nature Publishing Group
• Subjects: 631/1647/514/1949; 631/250/2504/342; 692/308/53/2421; 692/420/256/1980; 692/699/255/1318; Bacteria; Bacteria - immunology; Bacterial diseases; Bacterial infections; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Blood; Bone marrow; Bone Marrow Cells - metabolism; Cancer Research; CD14 antigen; Clustering; Cohort Studies; Dendritic cells; Disease control; Epigenesis, Genetic; Etiology; Gene expression; Gene Expression Profiling; Gene sequencing; Genetic aspects; Genomics; Geographical locations; Humans; Immune response; Immune system; Infectious Diseases; Letter; Leukocytes (mononuclear); Metabolic Diseases; Molecular Medicine; Monocytes; Monocytes - metabolism; Neurosciences; Patient outcomes; Peripheral blood mononuclear cells; Phenotypes; Reproducibility of Results; Ribonucleic acid; RNA; ROC Curve; Sepsis; Sepsis - blood; Sepsis - genetics; Sepsis - immunology; Sepsis - microbiology; Sequence Analysis, RNA; Signatures; Surface markers; Transcription; Transcription, Genetic; Transcriptomics; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-020-0752-4

Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis ( n  = 29) across three clinical cohorts with corresponding controls ( n   =  36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14 + monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n   =  1,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis. Single-cell transcriptomic analysis identifies a distinct gene signature associated with peripheral monocyte populations that distinguishes people with sepsis from those with sterile inflammation and uninfected controls.