Abstract
BackgroundCaenorhabditis elegans has emerged over the last decade as a useful model for the study of innate immunity. Its infection with the pathogenic fungus Drechmeria coniospora leads to the rapid up-regulation in the epidermis of genes encoding antimicrobial peptides. The molecular basis of antimicrobial peptide gene regulation has been previously characterized through forward genetic screens. Reverse genetics, based on RNAi, provide a complementary approach to dissect the worm’s immune defenses.ResultsWe report here the full results of a quantitative whole-genome RNAi screen in C. elegans for genes involved in regulating antimicrobial peptide gene expression. The results will be a valuable resource for those contemplating similar RNAi-based screens and also reveal the limitations of such an approach. We present several strategies, including a comprehensive class clustering method, to overcome these limitations and which allowed us to characterize the different steps of the interaction between C. elegans and the fungus D. coniospora, leading to a complete description of the MAPK pathway central to innate immunity in C. elegans. The results further revealed a cross-tissue signaling, triggered by mitochondrial dysfunction in the intestine, that suppresses antimicrobial peptide gene expression in the nematode epidermis.ConclusionsOverall, our results provide an unprecedented system’s level insight into the regulation of C. elegans innate immunity. They represent a significant contribution to our understanding of host defenses and will lead to a better comprehension of the function and evolution of animal innate immunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0256-3) contains supplementary material, which is available to authorized users.
Highlights
Caenorhabditis elegans has emerged over the last decade as a useful model for the study of innate immunity
We have demonstrated that a second family of antimicrobial peptide (AMP) genes, called caenacins, including cnc-2, are controlled by a cell non-autonomous signal transduction pathway, wherein the nematode TGF-ß, DBL-1, produced in neurons, modulates cnc-2 expression in the epidermis following D. coniospora infection
We focused on the large family of worm G-protein coupled receptor (GPCR) genes and defined a key role for DCAR-1 that acts as a “damage-associated molecular pattern” receptor, acting upstream of the p38 MAPK cascade [20]
Summary
Caenorhabditis elegans has emerged over the last decade as a useful model for the study of innate immunity. Infection of Caenorhabditis elegans by its natural fungal pathogen Drechmeria coniospora provokes an innate immune response characterized by the expression of antimicrobial peptide (AMP) genes in the worm epidermis [1]. We have demonstrated that a second family of AMP genes, called caenacins (cnc), including cnc-2, are controlled by a cell non-autonomous signal transduction pathway, wherein the nematode TGF-ß, DBL-1, produced in neurons, modulates cnc-2 expression in the epidermis following D. coniospora infection. This pathway does not, influence nlp-29 expression [6], which up until now has been found to be controlled cell-autonomously in the epidermis [3, 5, 7,8,9]. In C. elegans, the disruption of cellular homeostasis in one tissue can influence a stress response in a distant tissue (reviewed in [10,11,12]); whether this is the case for nlp-29 remains an open question
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