Single-type neuron transcriptomics uncovers cell-type-specific regulators of host defense in Caenorhabditis elegans

SUMMARY Understanding how the nervous system regulates immune responses requires insight into how individual neurons respond to infection. In Caenorhabditis elegans , sensory neurons such as ASH play important roles in modulating innate immunity; however, the molecular mechanisms operating within these neurons remain poorly defined. Previous transcriptomic studies have relied on whole-animal RNA sequencing, which lacks the cellular resolution needed to detect neuron-specific signaling programs. Here, we performed single-type neuron transcriptomic profiling to characterize gene expression in ASH neurons from infected and uninfected animals. We found that ASH neurons undergo extensive transcriptional remodeling in response to pathogen exposure, with enrichment of genes associated with G protein-coupled receptor signaling, neuropeptide activity, and sensory transduction. Notably, we identified genes, including zig-3 and F36F2 . 8 , that are strongly induced in ASH neurons but are not detected in whole-animal transcriptomic datasets. Functional analysis using ASH-specific RNA interference demonstrated that knockdown of either gene significantly reduces survival during Pseudomonas aeruginosa infection, whereas whole-animal RNAi produces no detectable phenotype. Together, these findings reveal that cell-type-resolved transcriptomics can uncover functionally important regulators of host defense that are masked in bulk analyses and provide new insight into neuron-intrinsic mechanisms of neuroimmune regulation.