A novel Gasdermin D C-terminal neo-epitope as a biomarker for pyroptosis in sepsis

Gasdermin D (GSDMD)-mediated pyroptosis, a critical component of the innate immune response, is triggered by pathogenic microbial infections and plays a key role in host defense mechanisms. This process involves the cleavage of GSDMD by inflammatory caspases, releasing carboxy-terminal fragments (GSDMD-CT). Monitoring GSDMD-CT levels represents a promising approach for inflammatory diseases, including sepsis and systemic inflammatory response syndrome (SIRS).

We developed an immunoassay to measure plasma GSDMD-CT concentrations in 109 healthy individuals, 137 patients with SIRS, and 100 patients with sepsis. The diagnostic utility of GSDMD-CT in distinguishing sepsis from SIRS or healthy controls was assessed using receiver operating characteristic (ROC) analysis, alongside correlations with procalcitonin (PCT), and C-reactive protein (CRP).

Plasma GSDMD-CT levels were significantly elevated in patients with sepsis compared to healthy control and SIRS groups. ROC analysis demonstrated an area under the curve of 0.870, with a sensitivity of 91.0% and specificity of 60.6% for differentiating sepsis from healthy controls. Comparable performance was observed in distinguishing SIRS from healthy controls. Diagnostic accuracy was further enhanced when GSDMD-CT was combined with CRP. Strikingly, GSDMD-CT mirrored the kinetic profile of PCT in antibiotic-treated patients with bacterial infections.

The GSDMD-CT assay demonstrates high sensitivity as a biomarker, offering potential for early and differential diagnosis of sepsis across diverse pathogens.