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

Darden, Dijoia B; Bacher, Rhonda; Brusko, Todd M.; Knight, Parker; Hawkins, Russell B.; Cox, Michael C.; Dirain, Marvin; Ungaro, Ricardo; Nacionales, Dina C.; Rincón, Jaimar; Gauthier, Marie-Pierre; Kladde, Michael P.; Brusko, Todd M.; Moore, Frederick A.; Brakenridge, Scott C.; Mohr, Alicia M.; Moldawer, Lyle L.; Efron, Philip A.

doi:10.1097/shk.0000000000001671

Cited by 41 publications

(45 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, we were only able to analyze immune cell transcriptome patterns at one time point in late sepsis. Future transcriptomic analysis with more time points is warranted to analyze time-dependent genomic expression patterns of late sepsis in sepsis survivors (14). Finally, this is a descriptive study.…”

Section: Discussionmentioning

confidence: 99%

“…Understanding the pathobiology of leukocytes in late sepsis, as well as the dysfunctional hematopoiesis that leads to this immune dyscrasia, will be vital to any successful immunomodulation of sepsis survivors. Our laboratory has previously published a pilot study specifically evaluating myeloid-derived suppressor cells in surgical sepsis survivors (14). However, we realized that studies on nonmyeloid immune cell subtypes chronically after sepsis are lacking.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, increasing evidence have found that the alternation of microbiota, so-called dysbiosis, may have an impact on the outcome of critically ill patients for at least 3 months [ 7 , 9 , 30 ]. Darden et al used single-cell RNAseq and myeloid-enriched peripheral blood mononuclear cells among critically ill surgical patients on day-21 after the sepsis to characterise the immunosuppressive transcriptome of myeloid-derived suppressor cells in critically ill surgical patients with CCI [ 31 , 32 ]. We speculate that alternation of microbiota might account for the relatively strong association between culture positivity and risk of mortality among non-infectious critically ill surgical patients, including those receiving cardiovascular surgery and patients without malignancy or metastatic tumour (Additional file 1 : Table S2).…”

Section: Discussionmentioning

confidence: 99%

The association between culture positivity and long-term mortality in critically ill surgical patients

Wong

et al. 2021

j intensive care

View full text Add to dashboard Cite

Background The long-term outcome is an essential issue in critically ill patients, and the identification of early determinant is needed for risk stratification of the long-term outcome. In the present study, we investigate the association between culture positivity during admission and long-term outcome in critically ill surgical patients. Methods We linked the 2015–2019 critical care database at Taichung Veterans General Hospital with the nationwide death registration files in Taiwan. We described the long-term mortality and proportion of culture positivity among enrolled subjects. We used a log-rank test to estimate survival curves between patients with and without positive cultures and a multivariable Cox proportional hazards regression model to determine hazard ratio (HR) and 95% confidence interval (CI). Results A total of 6748 critically ill patients were enrolled, and 32.5% (2196/6749) of them died during the follow-up period, with the overall follow-up duration was 1.8 ± 1.4 years. We found that 31.4% (2122/6748) of critically ill patients had at least one positive culture during the index admission, and the number of patients with positive culture in the blood, respiratory tract, urinary tract, skin and soft tissue and abdomen were 417, 1702, 554, 194 and 139, respectively. We found that a positive culture from any sites was independently associated with high long-term mortality (aHR 1.579, 95% CI 1.422–1.754) after adjusting relevant covariates, including age, sex, body-mass index, comorbidities, severity score, shock, early fluid overload, receiving mechanical ventilation and the need of renal replacement therapy for critical illness. Conclusions We linked two databases to identify that a positive culture during admission was independently correlated with increased long-term mortality in critically ill surgical patients. Our findings highlight the need for vigilance among patients with a positive culture during admission, and more studies are warranted to validate our findings and to clarify underlying mechanisms.

show abstract

“…Sepsis is a dysregulated systemic inflammatory response, which alters the innate and adaptive immune responses to microbial invasion and results in organ injury with mortality rates of 15–25% 40, 41 . Given significant sepsis disease heterogeneity, single cell transcriptomics offers an valuable approach to provide a better understanding of the molecular mechanisms of sepsis, however, from over 1000 single-cell transcriptomics studies have been published to date 42 , only two studied sepsis 8, 43 . In those two studies, the authors focused on monocytes and myeloid-derived suppressor cells by sorting on specific surface markers.…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in human single cell transcriptional signatures during fatal sepsis

Qiu

Bonenfant

et al. 2021

Preprint

View full text Add to dashboard Cite

Systemic infections, especially in patients with chronic diseases, result in sepsis: an explosive, uncoordinated immune response that can lead to multisystem organ failure with a high mortality rate. Sepsis survivors and non-survivors oftentimes have similar clinical phenotypes or sepsis biomarker expression upon diagnosis, suggesting that the dynamics of sepsis in the critical early stage may have an impact on these opposite outcomes. To investigate this, we designed a within-subject study of patients with systemic gram-negative bacterial sepsis with surviving and fatal outcomes and performed single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis recognition and 6 hours. We observed that the largest sepsis-induced expression changes over time in surviving versus fatal sepsis were in CD14+ monocytes, including gene signatures previously reported for sepsis outcomes. We further identify changes in the metabolic pathways of both monocytes and platelets, the emergence of erythroid precursors, and T cell exhaustion signatures, with the most extreme differences occurring between the non-sepsis control and the sepsis non-survivor. Our single-cell observations are consistent with trends from public datasets but also reveal specific effects in individual immune cell populations, which change within hours. In conclusion, this pilot study provides the first single-cell results with a repeated measures design in sepsis to analyze the temporal changes in the immune cell population behavior in surviving or fatal sepsis. These findings indicate that tracking temporal expression changes in specific cell-types could lead to more accurate predictions of sepsis outcomes. We also identify molecular pathways that could be therapeutically controlled to improve the sepsis trajectory toward better outcomes.

show abstract

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

Cited by 41 publications

References 48 publications

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

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

The association between culture positivity and long-term mortality in critically ill surgical patients

Dynamic changes in human single cell transcriptional signatures during fatal sepsis

Contact Info

Product

Resources

About