NEUROIMMUNE CONTROL OF SICKNESS BEHAVIOR

Sickness behavior is a coordinated set of physiological and behavioral adaptations to infection that profoundly reshape organismal function. Although these responses are widely attributed to immune-derived signals, how dedicated sensory circuits couple infected peripheral organs to other organs and the brain remains unresolved. Here, we reveal a lung-brain neuroimmune circuit that actively instructs sickness behavior during respiratory infection. As such, infection rapidly induces hypothermia and a conserved behavioral state characterized by suppressed locomotion, social withdrawal, and diminished exploratory drive. Mechanistically, TRPV1⁺ vagal sensory neurons innervating the lung selectively control hypothermia and behavior while sparing infection-induced weight loss. Surprisingly, this functional dissociation reveals a modular neural architecture for sickness responses that operates independently of canonical peptidergic neurotransmitters, including CGRP and Substance P. In addition, genetic disruption of bacterial virulence programs and the use of immunodeficient hosts exclude canonical pathogen- and immune-derived signals as primary drivers of neuronal activation, instead implicating an alternative host-pathogen interface that engages sensory pathways to regulate brain state. Together, these findings establish peripheral sensory neurons as organizers of infection-induced sickness behavior, redefining it as a neuronally encoded response that coordinates behavioral states and cross-organ communication.