Metabolic and post-translational modifications in sepsis-associated immune dysfunction: a conceptual framework

Area of Science:

• Immunology
• Molecular Biology
• Systems Biology

Background:

• Sepsis involves immune signal transduction collapse.
• Post-translational modifications (PTMs) regulate immune response dynamics.
• The shift from cytokine storm to immune paralysis in sepsis is poorly understood at a molecular level.

Purpose of the Study:

• To propose a metabolic-PTM temporal switch model for sepsis-induced immune dysfunction.
• To explain the molecular logic behind the transition in immune signaling during sepsis.
• To provide a framework for understanding context-dependent immune dysfunction and intervention outcomes.

Main Methods:

• Conceptual modeling integrating PTMs, cellular metabolism, and chromatin structure.
• Analysis of PTM patterns (phosphorylation, ubiquitination, lactylation) across sepsis stages.
• Consideration of metabolic availability and chromatin accessibility as constraints on signaling.

Main Results:

• A model is proposed where immune signaling is rewired by PTM configurations influenced by metabolism and chromatin.
• Early sepsis: Permissive metabolism and open chromatin favor reversible PTMs amplifying innate immunity.
• Late sepsis: Metabolic stress and chromatin condensation promote persistent PTMs, leading to immune refractoriness.

Conclusions:

• The metabolic-PTM temporal switch model explains immune dysfunction in sepsis as a loss of signaling competence, not just attenuation.
• This framework clarifies why immune stimulation often fails in late-stage sepsis due to impaired signaling architecture.
• Understanding context-associated PTM patterns offers guidance for interpreting sepsis outcomes and designing interventions.