The expression of a diverse array of olfactory receptors within sensory neurons is essential for metazoans to survive in microbe-rich environments. For example, amphid neurons in the head of the nematode C. elegans sample the environment and program rapid changes in locomotion, which allows nematodes to forage decomposing organic matter for bacterial food sources and avoid potential pathogens. Thus, C. elegans provides an experimental platform to understand how the development of sensory neurons is integrated with the physiology of the organism as a whole.

Olfactory neurons allow animals to discriminate nutritious food sources from potential pathogens. From a forward genetic screen, we uncovered a surprising requirement for the olfactory neuron gene olrn-1 in the regulation of intestinal epithelial immunity in Caenorhabditis elegans. During nematode development, olrn-1 is required to program the expression of odorant receptors in the AWC olfactory neuron pair. Here, we show that olrn-1 also functions in AWC neurons in the cell non-autonomous suppression of the canonical p38 MAPK PMK-1 immune pathway in the intestine. Low activity of OLRN-1, which activates the p38 MAPK signaling cassette in AWC neurons during larval development, also de-represses the p38 MAPK PMK-1 pathway in the intestine to promote immune effector transcription, increased clearance of an intestinal pathogen, and resistance to bacterial infection. These data reveal an unexpected connection between olfactory receptor development and innate immunity and show that anti-pathogen defenses in the intestine are developmentally programmed.

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