Lalsiamthara, J. | bioRxiv Science

bioRxiv2026

NMDA Receptor Subunit NMR-2 Regulates Pathogen-Induced Immune Responses via the Nervous System in C. elegans

Neural control of innate immunity must balance restraint of basal immune activity with rapid activation upon pathogen encounter. Glutamate, the primary excitatory neurotransmitter in the nervous system, has been implicated in several neurological disorders associated with inflammation, suggesting a potential link to immune regulation. However, how glutamatergic signaling contributes to immune balance remains unknown. Here, we demonstrated that the NMDA-type ionotropic glutamate receptor subunit NMR-2, a component of the NMDA receptor complex, acts in the C. elegans nervous system as a key regulator of pathogen-induced immune responses. Loss of nmr-2 enhanced resistance to Staphylococcus aureus and Pseudomonas aeruginosa, without elevating basal immune gene expression. The pathogen-induced response controlled by NMR-2 required the conserved PMK-1/p38 MAPK, DAF-16/FOXO, and HLH-30/TFEB pathways. We identified the AVD interneuron as the site of action of NMR-2, where it integrates inputs from upstream sensory neurons ASE, ASK, AQR, and PQR. These findings uncover a neural circuit in which glutamatergic signaling distinguishes basal immune gene expression from pathogen-induced immune responses, revealing a mechanism that promotes effective defense without altering baseline immunity.

immunology↗

bioRxiv2022

Dissection of a sensorimotor circuit that regulates aversion to odors and pathogenic bacteria in C. elegans by whole-brain simulation

Altering behavior to reduce pathogen exposure is a key line of defense against pathogen attack for nearly all animals. The use of Caenorhabditis elegans bacterial infection models have allowed for many insights into the molecular mechanisms of behavioral immunity. However, the neural circuitry between chemosensory neurons that sense pathogenic bacterial cues and the motor neurons responsible for avoidance-associated locomotion remains unknown. We found that backward locomotion was a component of learned pathogen avoidance, as animals pre-exposed to Pseudomonas aeruginosa or Enterococcus faecalis showed reflexive aversion to drops of the bacteria, requiring ASI, AWB, and AWC neurons and ASE, AWB, and AWC neurons, respectively. This response also involved intestinal distention and, for E. faecalis, required expression of TRPM channels in the intestine and excretory system. Using whole-brain simulation and functional assays, we uncovered a sensorimotor circuit governing learned reflexive aversion. This behavior is controlled by a four-layer neural circuit composed of olfactory neurons, interneurons, and motor neurons that control backward locomotion crucial for learned reflexive aversion to pathogenic bacteria, learned avoidance, and a repulsive odor. The discovery of a complete sensorimotor circuit for reflexive aversion demonstrates the utility of using the C. elegans connectome and computational modeling in uncovering new neuronal regulators of behavior.

neuroscience↗