Editors' ChoiceHost-Pathogen Interactions

TLR signaling mediates pathogen avoidance

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Sci. Signal.  08 Sep 2015:
Vol. 8, Issue 393, pp. ec254
DOI: 10.1126/scisignal.aad3632

Activation of Toll-like receptors (TLRs) by pathogen-associated molecular patterns triggers innate immune responses in both vertebrates and insects. However, in some invertebrates, such as the nematode Caenorhabditis elegans, TLR signaling does not induce innate immunity (see commentary by Kim). Brandt and Ringstad found that the single C. elegans TLR homolog TOL-1 nevertheless plays a role in pathogen defense by promoting the development of a pair of chemosensory neurons, the BAG neurons, which are sensitive to CO2 and O2. TOL-1 and PMK-3, a p38 mitogen-activated protein kinase (MAPK), were required cell-autonomously during embryonic and larval development for proper morphology of the BAG neurons, for normal expression of BAG-specific markers, and for animals to migrate down a CO2 gradient. Genetic experiments placed TOL-1 upstream of the MAPKKK MOM-4, which is homologous to the mammalian TLR effector TAK (TGF-β–activated kinase), and PMK-3 and indicated that homologs of the mammalian TLR effectors IRAK (interleukin receptor–activated kinase), TRAF (TNF receptor–associated factor), and IκB (inhibitor of κB) were also involved in specification and function of BAG neurons. In experiments using a genetically-encoded calcium indicator, BAG neurons in tol-1 mutants showed reduced calcium signaling in response to CO2 compared with BAG neurons in wild-type animals. In contrast to wild-type worms, tol-1 or pmk-3 mutants did not avoid pathogenic bacteria, and expression tol-1 or pmk-3 in the BAG neurons in their respective mutants restored pathogen avoidance. Wild-type worms did not avoid heat-killed pathogenic bacteria, suggesting that they only avoid metabolically active pathogens. CO2 alone did not trigger pathogen avoidance, but CO2-mediated stimulation of BAG neurons in combination with bacterial-derived odorants that are sensed by other neurons induced pathogen avoidance. These results suggest that BAG neurons are necessary for worms to detect dense bacterial populations but that other chemosensory neurons enable worms to discriminate between pathogenic and nonpathogenic bacteria, the latter of which are a food for these worms. Thus, instead of triggering innate immunity, TOL-1 promotes the development of chemosensory neurons that help worms avoid contacting pathogens in the first place.

J. P. Brandt, N. Ringstad, Toll-like receptor signaling promotes development and function of sensory neurons required for a C. elegans pathogen-avoidance behavior. Curr. Biol. 25, 2228–2237 (2015). [PubMed]

D. H. Kim, Signal transduction: A different kind of Toll is in the BAG. Curr. Biol. 25, R767–R769 (2015). [PubMed]