Neuronal regulation of infection recovery prevents pathogenic stress and tissue damage

Abstract

Neural regulation of immunity is increasingly recognized, yet how the nervous system promotes infection resolution after pathogen clearance remains poorly understood. Using Caenorhabditis elegans, we identify the AIA interneurons as key regulators of both infection and recovery. Acute silencing or genetic ablation of AIA neurons during Salmonella enterica infection reduces host survival, causes excessive 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), and exacerbates intestinal tissue damage. Strikingly, selective silencing of AIA neurons after pathogen clearance markedly impairs recovery, demonstrating that neural activity is required not only for host defense but also for infection resolution. This defect is rescued by xbp-1, but not pmk-1 or daf-16, knockdown, identifying unresolved ER stress as the principal driver of post-infection mortality. Consistently, AIA silencing during recovery sustains UPR activation and worsens epithelial barrier damage. Together, our findings establish AIA interneurons as central regulators of immune homeostasis that promote infection resolution by limiting excessive ER stress and preserving tissue integrity.