1. A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis
- Author
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Marie Gauthier, Lyle L. Moldawer, Alicia M. Mohr, Xiaoru Dong, Azra Bihorac, Frederick A. Moore, Todd M. Brusko, Rhonda Bacher, Lauren S Kelly, Dina C. Nacionales, Tyler J. Loftus, Philip A. Efron, Ricardo Ungaro, Dijoia B Darden, Michael P. Kladde, Marvin L. Dirain, Jaimar Rincon, Maigan A. Brusko, and Brittany P Fenner
- Subjects
lymphocytes ,Adult ,Male ,Endotype ,Time Factors ,Myeloid ,Surviving Sepsis Campaign ,Immunology ,Inflammation ,sepsis ,Sepsis ,Transcriptome ,immune cells ,Immune system ,scRNA-seq ,medicine ,Humans ,Immunology and Allergy ,RNA-Seq ,Lymphopoiesis ,Original Research ,Aged ,Aged, 80 and over ,business.industry ,Gene Expression Profiling ,Bacterial Infections ,Dendritic Cells ,RC581-607 ,Middle Aged ,medicine.disease ,chronic critical illness ,Phenotype ,medicine.anatomical_structure ,Mycoses ,Case-Control Studies ,Female ,Immunologic diseases. Allergy ,Single-Cell Analysis ,medicine.symptom ,business - Abstract
BackgroundWith the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adverse long-term outcomes and 1-year mortality. Although the pathobiology of CCI remains undefined, emerging evidence suggests a post-sepsis state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, as well as downstream leukocyte dysfunction. Our goal was to use single-cell RNA sequencing (scRNA-seq) to perform a detailed transcriptomic analysis of lymphoid-derived leukocytes to better understand the pathology of late sepsis.MethodsA mixture of whole blood myeloid-enriched and Ficoll-enriched peripheral blood mononuclear cells from four late septic patients (post-sepsis day 14-21) and five healthy subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq).ResultsWe identified unique transcriptomic patterns for multiple circulating immune cell subtypes, including B- and CD4+, CD8+, activated CD4+ and activated CD8+ T-lymphocytes, as well as natural killer (NK), NKT, and plasmacytoid dendritic cells in late sepsis patients. Analysis demonstrated that the circulating lymphoid cells maintained a transcriptome reflecting immunosuppression and low-grade inflammation. We also identified transcriptomic differences between patients with bacterial versus fungal sepsis, such as greater expression of cytotoxic genes among CD8+ T-lymphocytes in late bacterial sepsis.ConclusionCirculating non-myeloid cells display a unique transcriptomic pattern late after sepsis. Non-myeloid leukocytes in particular reveal a host endotype of inflammation, immunosuppression, and dysfunction, suggesting a role for precision medicine-guided immunomodulatory therapy.
- Published
- 2021