Circadian-shaped immune variability predicts infection outcome.

Abstract

Disease risk and severity are influenced by genetics, epigenetics, and environmental factors. However, immune responses vary even among genetically similar or related individuals, shaped by inherited and noninherited factors. Using <i>Caenorhabditis elegans</i>, we found that pathogen susceptibility can be predicted by preinfection biomarkers. Individuals with high-basal expression of <i>irg-5</i>, an infection response gene regulated by the p38 mitogen-activated protein kinase-1 (PMK-1) pathway, were more susceptible to <i>Pseudomonas aeruginosa</i> infection. A genome-wide screen identified the myeloid ecotropic viral integration site-1 (MEIS) homeobox protein UNC-62 as a regulator of <i>irg-5</i> expression, acting through PMK-1 and GATA binding erythroid-like transcription factor (ELT-2). Further analysis revealed that maternal circadian timing shaped offspring immune heterogeneity and inhibition of clock genes eliminated the effects induced by maternal timing. These findings highlight circadian-driven immune variability as a potential adaptive strategy for resilience against infection.