Neuronal regulation of infection recovery prevents pathogenic stress and tissue damage

Abstract Neural regulation of innate immunity is increasingly recognized, yet how the nervous system controls immune resolution after pathogen clearance remains poorly understood. Using Caenorhabditis elegans as a genetically tractable model, we identify the AIA interneurons as critical regulators of both infection-phase homeostasis and post-infection recovery. Acute silencing or genetic ablation of AIA neurons during Salmonella enterica infection results in reduced host survival with heightened activation of conserved immune and stress pathways, including PMK-1/p38 MAPK, insulin/IGF-1 signaling, and the XBP-1-mediated unfolded protein response (UPR). AIA-deficient animals exhibit excessive immune and stress response gene expression and increased intestinal tissue damage, demonstrating that immune hyperactivation is detrimental. Strikingly, selective silencing of AIA neurons during the recovery phase after pathogen clearance significantly impairs survival, revealing that neural activity is required not only for defense but also for resolution. This recovery defect is rescued by knockdown of xbp-1 , but not pmk-1 or daf-16 , indicating that unresolved ER stress is the principal driver of post-infection mortality. Consistently, AIA silencing during recovery sustains UPR activation and exacerbates epithelial barrier damage. Together, our findings establish AIA interneurons as central coordinators of immune homeostasis that limit pathological stress responses during infection and actively promote infection resolution. These findings provide mechanistic insight into how the nervous system not only restrains excessive immune and stress responses during infection but also actively resolves stress signaling and preserves tissue integrity during post-infection recovery.