Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission

Sonia Y Velásquez; Anna Coulibaly; Carsten Sticht; Jutta Schulte; Bianka Hahn; Timo Sturm; Roman Schefzik; Manfred Thiel; Holger A Lindner

doi:10.3389/fimmu.2022.864835

Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission

Front Immunol. 2022 Jun 30:13:864835. doi: 10.3389/fimmu.2022.864835. eCollection 2022.

Authors

Affiliations

¹ Department of Anesthesiology and Surgical Intensive Care Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Next Generation Sequencing Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Mannheim Institute of Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Abstract

Infection can induce granulopoiesis. This process potentially contributes to blood gene classifiers of sepsis in systemic inflammatory response syndrome (SIRS) patients. This study aimed to identify signature genes of blood granulocytes from patients with sepsis and SIRS on intensive care unit (ICU) admission. CD15⁺ cells encompassing all stages of terminal granulocytic differentiation were analyzed. CD15 transcriptomes from patients with sepsis and SIRS on ICU admission and presurgical controls (discovery cohort) were subjected to differential gene expression and pathway enrichment analyses. Differential gene expression was validated by bead array in independent sepsis and SIRS patients (validation cohort). Blood counts of granulocyte precursors were determined by flow cytometry in an extension of the validation cohort. Despite similar transcriptional CD15 responses in sepsis and SIRS, enrichment of canonical pathways known to decline at the metamyelocyte stage (mitochondrial, lysosome, cell cycle, and proteasome) was associated with sepsis but not SIRS. Twelve of 30 validated genes, from 100 selected for changes in response to sepsis rather than SIRS, were endo-lysosomal. Revisiting the discovery transcriptomes revealed an elevated expression of promyelocyte-restricted azurophilic granule genes in sepsis and myelocyte-restricted specific granule genes in sepsis followed by SIRS. Blood counts of promyelocytes and myelocytes were higher in sepsis than in SIRS. Sepsis-induced granulopoiesis and signature genes of early terminal granulocytic differentiation thus provide a rationale for classifiers of sepsis in patients with SIRS on ICU admission. Yet, the distinction of this process from noninfectious tissue injury-induced granulopoiesis remains to be investigated.

Keywords: gene classifier; granulocytes; infections; sepsis; systemic inflammation; transcriptome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Granulocytes
Humans
Intensive Care Units
Prognosis
Sepsis* / diagnosis
Sepsis* / genetics
Systemic Inflammatory Response Syndrome* / diagnosis
Systemic Inflammatory Response Syndrome* / genetics