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Background <p>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.</p> Objectives <p>To identify the immunological signatures that distinguish MALS and immune paralysis.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>Our findings shed light on the heterogeneous immune landscape underlying sepsis and provide opportunities for patient stratification for future therapeutic development.</p>

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Distinct transcriptomic signatures discriminate hyperinflammation from immune paralysis in sepsis: a single-cell RNA sequencing study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Inge Grondman,
  • Valerie A. C. M. Koeken,
  • Tristan Couwenbergh,
  • Athanasios Karageorgos,
  • Wenchao Li,
  • Nikolaos Antonakos,
  • Bowen Zhang,
  • Georgia Damoraki,
  • Wouter A. van der Heijden,
  • Cheng-Jian Xu,
  • Evangelos J. Giamarellos-Bourboulis,
  • Yang Li,
  • Mihai G. Netea

摘要

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.