The DBL-1/TGF-β signaling pathway regulates pathogen-specific innate immune responses inC. elegans

Abstract

Innate immunity in animals is orchestrated by multiple cell signaling pathways, including the TGF-β; superfamily pathway. While the role of TGF-β signaling in innate immunity has been clearly identified, the requirement for this pathway in generating specific, robust responses to different bacterial challenges has not been characterized. Here, we address the role of DBL-1/TGF-β in regulating signature host defense responses to a wide range of bacteria in C. elegans. This work reveals a role of DBL-1/TGF-β in animal survival, organismal behaviors, and molecular responses in different environments. Additionally, we identify a novel role for SMA-4/Smad that suggests both DBL-1/TGF-β-dependent and -independent functions in host avoidance responses. RNA-seq analyses and immunity reporter studies indicate DBL-1/TGF-β differentially regulates target gene expression upon exposure to different bacteria. Furthermore, the DBL-1/TGF-β pathway is itself differentially affected by the bacteria exposure. Collectively, these findings demonstrate bacteria-specific host immune responses regulated by the DBL-1/TGF-β signaling pathway.

Endocytic coelomocytes are required for lifespan extension by axenic dietary restriction

“…In our hands, dbl-1(nk3) displays a 13% longer FF lifespan and under ADR becomes slightly shorter lived than wild type, now displaying a small but significant reduction in lifespan of 6% ( Fig 2A ). However, our FF result opposes observations by others [ 33 , 35 – 38 ], and previous work points towards an interaction effect between FUdR–used in all our experiments to avoid progeny–and dbl-1 mutation [ 33 , 38 ]. We confirmed this interaction effect for FF conditions, with a lower concentration of FUdR resulting in a shorter lifespan ( S2 Fig ).…”

TGF-β pathways in aging and immunity: lessons from Caenorhabditis elegans

“…It was later found that production of DBL-1 in ASI and ASJ sensory neurons is prevented by AMPylase FIC-1 overexpression, consistent with their decreased pathogen avoidance (Hernandez-Lima et al, 2022). Loss of dbl-1 has also been seen to have an increased avoidance of E. coli, supporting how OP50 may have increased pathogenicity in these animals compared to WT (Madhu and Gumienny, 2021). In a panel of three Gram-positive bacteria and three Gram-negative bacteria, dbl-1 mutants displayed strong avoidance to all three Gram-negative bacteria, and a mild response to one of three Gram-positive bacteria.…”

“…In the response to pathogenic fungus Drechmeria coniospora , SMA-3 but not SMA-2 or SMA-4 is required, indicating the existence of non-canonical signaling of R-Smad without a Co-Smad ( Zugasti and Ewbank, 2009 ). In trying to identify patterns in how DBL-1 signaling responds to Gram-negative versus Gram-positive bacteria, one study tested a panel of three Gram-negative bacteria, and three Gram-positive bacteria, and found trends in DBL-1 pathway activity ( Madhu and Gumienny, 2021 ). Using an integrated fluorescent DBL-1 reporter, they found an induction of DBL-1 signaling on Gram-negative bacteria, while no fluorescence was seen on Gram-positive bacteria.…”

“…Unexpectedly, loss of SMA-4 had the opposite effect: a severe avoidance response to all three Gram-positive bacteria, correlated with increased SMA-4 expression. This led the authors to hypothesize that while the canonical pathway was involved in responding to all three Gram-negative bacteria, SMA-4 may act independently of DBL-1 in response to some Gram-positive bacteria, perhaps functioning with another pathway ( Madhu and Gumienny, 2021 ). Further studies using a larger bacterial panel would be interesting, and instrumental to make stronger conclusions.…”

“…This study was conducted on OP50, so it is not known whether these effects change on more pathogenic bacteria. Later work demonstrated that loss of DBL-1 results in decreased pharyngeal pumping on select pathogens: Klebsiella oxytoca , S. marcescens , E. faecalis , or S. epidermidis ( Madhu and Gumienny, 2021 ), suggesting that DBL-1 may be required for the pharynx to function correctly on some pathogens. sma-3 mutants have been shown to have decreased pharyngeal pumping on P. luminescens , which likely contributes to their increased infection susceptibility ( Ciccarelli et al, 2023a ).…”