Distinct transcriptomic signatures discriminate hyperinflammation from immune paralysis in sepsis: a single-cell RNA sequencing study.
9 affiliations
- 1Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein 8, Nijmegen, 6525GA, The Netherlands.
- 2Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.
- 3TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany.
- 4Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, The Netherlands.
- 5Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Geert Grooteplein 8, Nijmegen, 6525GA, The Netherlands. [email protected].
- 64th Department of Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.
- 7Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
- 8Hellenic Institute for the Study of Sepsis, Athens, Greece.
- 9Department of Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
Abstract
Background
Sepsis is a highly heterogeneous syndrome characterized by variable immune dysregulation states, including hyperinflammation and immunosuppression. Previous immunotherapy attempts in sepsis have largely failed, likely due to a "one-size-fits-all" approach that ignores each patient's immune status. The recent ImmunoSep randomized clinical trial demonstrated that precision immunotherapy guided by the presence of either macrophage activation-like syndrome (MALS) or immune paralysis can improve early organ dysfunction in sepsis patients. However, the molecular mechanisms underlying these immune endotypes remain unclear.Objectives
To identify the immunological signatures that distinguish MALS and immune paralysis.Methods
We used single-cell RNA sequencing to profile circulating leukocytes of 6 healthy controls and 16 sepsis patients classified as MALS, immune paralysis or unclassified (when criteria for neither of these two immune endotypes were applicable). Classification was based on surrogate biomarkers ferritin and HLA-DR expression on monocytes. Thereafter, the transcriptional programs of these groups were compared.Results
Pronounced differences were detected mainly in the transcriptional signature of monocytes from these patients, with a clear distinction between MALS and immune paralysis. Unsupervised clustering analysis revealed the existence of MALS-specific monocyte clusters, as well as one sepsis-specific monocyte cluster that was linked to greater comorbidity burden and may reflect increased clinical vulnerability in sepsis. These findings were validated in two independent cohorts, in which urosepsis was characterized by heterogeneous MALS and immune paralysis monocyte signatures. Moreover, MALS-specific monocyte clusters showed overlapping transcriptional signatures with severe COVID-19.Conclusions
Our findings shed light on the heterogeneous immune landscape underlying sepsis and provide opportunities for patient stratification for future therapeutic development.
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BibTeX
@article{grondman2026distinct,
title = {{Distinct transcriptomic signatures discriminate hyperinflammation from immune paralysis in sepsis: a single-cell RNA sequencing study.}},
author = {Inge Grondman and Valerie A C M Koeken and Tristan Couwenbergh and Athanasios Karageorgos and Wenchao Li and Nikolaos Antonakos and Bowen Zhang and Georgia Damoraki and Wouter A van der Heijden and Cheng-Jian Xu and Evangelos J Giamarellos-Bourboulis and Yang Li and Mihai G Netea},
journal = {Critical care (London, England)},
year = {2026},
month = aug,
doi = {10.1186/s13054-026-06229-w},
url = {https://europepmc.org/article/MED/42972580},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct transcriptomic signatures discriminate hyperinflammation from immune paralysis in sepsis: a single-cell RNA sequencing study.
AU - Inge Grondman
AU - Valerie A C M Koeken
AU - Tristan Couwenbergh
AU - Athanasios Karageorgos
AU - Wenchao Li
AU - Nikolaos Antonakos
AU - Bowen Zhang
AU - Georgia Damoraki
AU - Wouter A van der Heijden
AU - Cheng-Jian Xu
AU - Evangelos J Giamarellos-Bourboulis
AU - Yang Li
AU - Mihai G Netea
PY - 2026
DA - 2026/08/01
JO - Critical care (London, England)
DO - 10.1186/s13054-026-06229-w
UR - https://europepmc.org/article/MED/42972580
AB - Background Sepsis is a highly heterogeneous syndrome characterized by variable immune dysregulation states, including hyperinflammation and immunosuppression. Previous immunotherapy attempts in sepsis have largely failed, likely due to a "one-size-fits-all" approach that ignores each patient's immune status. The recent ImmunoSep randomized clinical trial demonstrated that precision immunotherapy guided by the presence of either macrophage activation-like syndrome (MALS) or immune paralysis can improve early organ dysfunction in sepsis patients. However, the molecular mechanisms underlying these immune endotypes remain unclear.Objectives To identify the immunological signatures that distinguish MALS and immune paralysis.Methods We used single-cell RNA sequencing to profile circulating leukocytes of 6 healthy controls and 16 sepsis patients classified as MALS, immune paralysis or unclassified (when criteria for neither of these two immune endotypes were applicable). Classification was based on surrogate biomarkers ferritin and HLA-DR expression on monocytes. Thereafter, the transcriptional programs of these groups were compared.Results Pronounced differences were detected mainly in the transcriptional signature of monocytes from these patients, with a clear distinction between MALS and immune paralysis. Unsupervised clustering analysis revealed the existence of MALS-specific monocyte clusters, as well as one sepsis-specific monocyte cluster that was linked to greater comorbidity burden and may reflect increased clinical vulnerability in sepsis. These findings were validated in two independent cohorts, in which urosepsis was characterized by heterogeneous MALS and immune paralysis monocyte signatures. Moreover, MALS-specific monocyte clusters showed overlapping transcriptional signatures with severe COVID-19.Conclusions Our findings shed light on the heterogeneous immune landscape underlying sepsis and provide opportunities for patient stratification for future therapeutic development.
SN - 1364-8535
SN - 1466-609X
ER -