Long-term malaria exposure in pathogen-endemic environments is associated with distinct immune states

Abstract Long-term exposure to malaria may shape baseline immune function, yet its effects in healthy adults remain unclear. Here we show that healthy Kenyan adults living in regions with higher malaria transmission and broader infectious exposure have distinct baseline immune profiles. Using blood-cell gene expression and circulating immune mediators from 60 adults across regions with differing malaria endemicity, we identify 658 differentially expressed genes. Higher exposure is associated with increased expression of pathways related to B-cell activation, antigen presentation, immune regulation, and post-transcriptional RNA processing, alongside reduced inflammatory, chemotactic, and vascular gene programmes. Circulating immune mediators are modestly elevated despite reduced inflammatory gene expression, indicating a partial dissociation between systemic mediator levels and cellular transcription. Our findings show that long-term malaria exposure in pathogen-endemic environments is associated with a distinct immune state characterised by adaptive immune activation and restrained inflammatory transcription, which may influence responses to subsequent infections and vaccination.