Identification and validation of a purine metabolism-associated four-gene host signature for pediatric bacterial infection

Abstract

Abstract Host metabolic reprogramming is a hallmark of infection, yet its link to immune dysregulation in pediatric bacterial infection remains unclear. Using a pediatric Staphylococcus aureus infection cohort (GSE30119) and two independent validation datasets (GSE40396 and GSE25504), purine metabolism was identified as a consistently suppressed pathway associated with immune responses. Based on this pathway, a four-gene host signature was established through differential expression analysis, immune association analysis, and LASSO logistic regression. The signature distinguished bacterial infection from healthy and viral states across multiple cohorts, with better performance than the individual genes, and this performance was preserved in infant sepsis datasets. Immune deconvolution and pathway analyses linked the signature to a neutrophil-dominated innate inflammatory response with concurrent alterations in adaptive immunity. Single-cell RNA sequencing further indicated that these changes reflect both shifts in immune cell composition and coordinated transcriptional reprogramming. Expression of the signature genes was validated by quantitative PCR in pediatric clinical samples. The signature score was also associated with disease severity in infected patients. These findings identify a purine metabolism-related host signature that may support the stratification of pediatric bacterial infection and help clarify the association between metabolic alteration and immune dysregulation.