A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis.

Abstract

Background:

With 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.

Methods:

A 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).

Results:

We 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.

Conclusion:

Circulating 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.

• Authors: Dijoia B Darden, Xiaoru Dong, Maigan A Brusko, Lauren Kelly, Brittany Fenner, Jaimar C Rincon, Marvin L Dirain, Ricardo Ungaro, Dina C Nacionales, Marie Gauthier, Michael Kladde, Todd M Brusko, Azra Bihorac, Frederick A Moore, Tyler Loftus, Rhonda Bacher, Lyle L Moldawer, Alicia M Mohr, Philip A Efron
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 696536 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 34484194 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Darden, Dong, Brusko, Kelly, Fenner, Rincon, Dirain, Ungaro, Nacionales, Gauthier, Kladde, Brusko, Bihorac, Moore, Loftus, Bacher, Moldawer, Mohr and Efron.

Topics

• Adult
• Aged
• Aged, 80 and over
• Bacterial Infections (blood, genetics, immunology, microbiology)
• Case-Control Studies
• Dendritic Cells (immunology, metabolism, microbiology)
• Female
• Gene Expression Profiling
• Humans
• Lymphocytes (immunology, metabolism, microbiology)
• Male
• Middle Aged
• Mycoses (blood, genetics, immunology, microbiology)
• Phenotype
• RNA-Seq
• Sepsis (blood, genetics, immunology, microbiology)
• Single-Cell Analysis
• Time Factors
• Transcriptome