Unique lymphocyte transcriptomic profiles in septic patients with chronic critical illness

Area of Science:

• Immunology
• Genomics
• Critical Care Medicine

Background:

• Sepsis survivors face long-term morbidity and mortality, with chronic critical illness (CCI) indicating poor outcomes.
• Immune suppression is a hallmark of sepsis survivors, especially those with CCI, but requires detailed investigation at the cellular level.
• Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect immune heterogeneity in sepsis.

Purpose of the Study:

• To investigate the immune cell transcriptional patterns and functional states in sepsis survivors with different clinical trajectories.
• To identify molecular mechanisms underlying immune suppression in sepsis survivors who develop chronic critical illness (CCI).

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood lymphocytes from healthy individuals, acutely septic patients, and those with rapid recovery or CCI.
• Differential gene expression, pathway analyses, and functional assays (ELISpot, cytokine production, T-cell proliferation) were employed.
• Independent cohorts were used for validation of observed T-cell functional changes.

Main Results:

• Sepsis survivors with CCI exhibited altered lymphoid cell populations, with increased CD8+ T cells and NK cells.
• Transcriptomic analysis revealed T-cell and NK-cell activation alongside suppressed B-cell function, with signs of exhaustion in CD8+ TEM cells and NK cells.
• Functional assays confirmed T cells maintained proliferation but had reduced cytokine production, and early IFN-γ was lower in those who later developed CCI.

Conclusions:

• Sepsis survivors display distinct, time- and trajectory-dependent immune cell transcriptional profiles.
• Immune exhaustion in CD8+ TEM cells and NK cells is a key feature of sepsis patients developing CCI.
• Molecular insights into sepsis-induced immune alterations are vital for developing personalized immunotherapies.