Dataset Information

Single-Cell RNA-seq of Human Myeloid-Derived Suppressor Cells in Late Sepsis Reveals Multiple Subsets With Unique Transcriptional Responses: A Pilot Study.

ABSTRACT:

Background

Increased circulating myeloid-derived suppressor cells (MDSCs) are independently associated with poor long-term clinical outcomes in sepsis. Studies implicate subsets of MDSCs having unique roles in lymphocyte suppression; however, characterization of these cells after sepsis remains incomplete. We performed a pilot study to determine the transcriptomic landscape in MDSC subsets in sepsis using single-cell RNAseq (scRNA-seq).

Methods

A mixture of whole blood myeloid-enriched and Ficoll-enriched PBMCs from two late septic patients on post-sepsis day 21 and two control subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq).

Results

We successfully identified the three MDSC subset clusters-granulocytic (G-), monocytic (M-), and early (E-) MDSCs. Sepsis was associated with a greater relative expansion of G-MDSCs versus M-MDSCs at 21 days as compared to control subjects. Genomic analysis between septic patients and control subjects revealed cell-specific and common differential expression of genes in both G-MDSC and M-MDSC subsets. Many of the common genes have previously been associated with MDSC proliferation and immunosuppressive function. Interestingly, there was no differential expression of several genes demonstrated in the literature to be vital to immunosuppression in cancer-induced MDSC.

Conclusion

This pilot study successfully demonstrated that MDSCs maintain a transcriptomic profile that is immunosuppressive in late sepsis. Interestingly, the landscape in chronic critical illness is partially dependent on the original septic insult. Preliminary data would also indicate immunosuppressive MDSCs from late sepsis patients appear to have a somewhat unique transcriptome from cancer and/or other inflammatory diseases.

SUBMITTER: Darden DB

PROVIDER: S-EPMC8019679 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Host immune responses during late-onset sepsis (LOS) in very preterm infants are poorly characterised due to a complex and dynamic pathophysiology and challenges in working with small available blood volumes. We present here an unbiased transcriptomic analysis of whole peripheral blood from very preterm infants at the time of LOS. METHODS:RNA-Seq was performed on peripheral blood samples (6-29 days postnatal age) taken at the time of suspected LOS from very preterm infants <30 weeks gestational age. Infants were classified based on blood culture positivity and elevated C-reactive protein concentrations as having confirmed LOS (n = 5), possible LOS (n = 4) or no LOS (n = 9). Bioinformatics and statistical analyses performed included pathway over-representation and protein-protein interaction network analyses. Plasma cytokine immunoassays were performed to validate differentially expressed cytokine pathways. RESULTS:The blood leukocyte transcriptional responses of infants with confirmed LOS differed significantly from infants without LOS (1,317 differentially expressed genes). However, infants with possible LOS could not be distinguished from infants with no LOS or confirmed LOS. Transcriptional alterations associated with LOS included genes involved in pathogen recognition (mainly TLR pathways), cytokine signalling (both pro-inflammatory and inhibitory responses), immune and haematological regulation (including cell death pathways), and metabolism (altered cholesterol biosynthesis). At the transcriptional-level cytokine responses during LOS were characterised by over-representation of IFN-?/?, IFN-?, IL-1 and IL-6 signalling pathways and up-regulation of genes for inflammatory responses. Infants with confirmed LOS had significantly higher levels of IL-1? and IL-6 in their plasma. CONCLUSIONS:Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis.