The DBL-1/TGF-β signaling pathway regulates an array of behavioral, molecular, and physiological defenses in Caenorhabditis elegans



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Organisms possess mechanisms to protect themselves from environmental threats. Animals have innate immune responses that include behavioral, molecular, and physiological components. A conserved cell-cell signaling pathway, transforming growth factor-beta (TGF-β) signaling pathway, is a major regulator of innate immune responses in animals. However, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not previously been well characterized. We used the roundworm Caenorhabditis elegans, which has conserved innate immune responses and TGF-β signaling pathways, to address how organisms use TGF-β signaling to tailor immune responses to different environmental threats. We tested the requirement for DBL-1/TGF-β signaling in a diverse array of immune responses to a selected panel of Gram-negative and Gram-positive bacteria. We showed that robust, protective, and specific responses to different bacteria require functional DBL-1 signaling. Animals lacking DBL-1 were more susceptible to all test bacteria. We discovered that canonical DBL-1 signaling is required to suppress avoidance to Gram-negative bacteria, but non-canonical DBL-1 signaling represses the avoidance to Gram-positive bacteria. Furthermore, this work identified a novel role for SMA-4/co-Smad that is independent of the DBL-1 signaling pathway. This indicates that the DBL-1/TGF-β signaling pathway plays an important role in tailoring the animals’ innate immune responses to the bacterial threat. Additionally, to investigate the role of saposin-like antimicrobial proteins in response to different environmental threats, we characterized the regulation of spp-9 in response to the bacterial panel. We identified that spp-9 is affected by both bacterial exposure and by starvation. We reported that the pathogen-specific regulation of spp-9 expression was dependent on not only DBL-1/TGF-β signaling but also other innate immune signaling pathways including insulin-like and p38/MAP kinase. Lastly, to determine the role of DBL-1 signaling in regulating the epicuticle, a secreted lipid-rich barrier layer, we developed a method to isolate epicuticular lipids and characterized their composition. We showed that DBL-1 signaling regulates the composition and levels of both epicuticle and internal lipids. DBL-1 signaling also regulates expression of lipid metabolism genes. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.



DBL-1, SMA-2, SMA-3, SMA-4, Innate immunity, C. elegans, Behavior, E. cloacae, K. oxytoca, S. marcescens, E. faecalis, B. megaterium, S. epidermidis, Host response, Saposin-like proteins, SPP-9, TGF-β, Molecular fingerprint, Epicuticle, Fatty acids, Lipid composition