Age- and sex-dependent transcriptomic network alterations in sepsis

Area of Science:

• Genomics
• Immunology
• Systems Biology

Background:

• Sepsis is a life-threatening condition with high mortality, characterized by dysregulated immune responses to infection.
• Nonspecific symptoms and complex molecular underpinnings of sepsis hinder early diagnosis and effective therapeutic development.
• The influence of host factors like age and sex on sepsis heterogeneity remains unclear.

Purpose of the Study:

• To investigate the preservation and reorganization of baseline gene co-expression networks in sepsis.
• To determine how age and sex influence these gene networks during sepsis.
• To identify potential demographic-aware biomarkers for sepsis diagnosis and treatment.

Main Methods:

• Analysis of RNA sequencing data from Peripheral Blood Mononuclear Cells (PBMCs) of healthy and sepsis-affected individuals.
• Identification and characterization of co-expression gene modules.
• Association analysis of gene modules and hub genes with clinical data (age, sex, sepsis status).

Main Results:

• Sixteen co-expression modules were identified in healthy controls, with most preserved in sepsis.
• Four modules showed disrupted organization in sepsis, indicating selective network reprogramming.
• A specific 'green' module strongly associated with age, sex, and sepsis, containing key age- and sex-associated hub genes, enabled high diagnostic accuracy (AUC=0.988) via a multigene model.

Conclusions:

• Age and sex significantly shape the molecular architecture of sepsis by influencing gene co-expression networks.
• Network reprogramming in sepsis involves pathways related to chromatin remodeling, DNA repair, and immune responses, aligning with aging hallmarks.
• Demography-aware approaches are crucial for understanding sepsis biology and developing precision diagnostics and therapeutics.