Complement receptor 2 downregulation is associated with mortality in Staphylococcus aureus sepsis in both mice and humans.

Although sepsis is a leading cause of global mortality, the lack of reliable biomarkers hinders early risk stratification. Such biomarkers would facilitate timely and precise therapeutic interventions. Using a murine model of Staphylococcus aureus (S. aureus) sepsis, we performed transcriptomic analysis and identified numerous genes that distinguished survivors from fatal cases. The top 16 candidate genes were further evaluated in patients with severe invasive bacterial infections. Among these, complement receptor 2 (CR2) was significantly downregulated in deceased patients compared with survivors and healthy controls. The extent of CR2 downregulation was dependent on the administered dose of S. aureus. Time-course experiments conducted in infected mice showed progressive B-cell depletion and CR2 downregulation, correlating with disease severity. Importantly, CR2 downregulation was independent of complement factor 3, TLR2, and tumor necrosis (TNF)-α, but was reversed in infections with S. aureus strains that lacked sortase A and B, and restored by antibiotic treatment of the infected mice. Loss of CR2 expression may reflect B-cell activation followed by differentiation into plasmablasts and redistribution to secondary lymphoid organs. The present study suggests that CR2 downregulation is associated with severe infection and mortality in S. aureus sepsis and may represent a candidate biomarker of host immune dysregulation that warrants further validation in larger clinical cohorts.