A quantitative genome-wide RNAi screen in C. elegans for antifungal innate immunity genes

ABSTRACT In response to infection, Caenorhabditis elegans produces an array of antimicrobial proteins. To understand the C. elegans immune response, we have investigated the regulation of a large, representative sample of candidate antimicrobial genes. We found that all these putative antimicrobial genes are expressed in tissues exposed to the environment, a position from which they can ward off infection. Using RNA interference to inhibit the function of immune signaling pathways in C. elegans, we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes. We also show that different bacterial pathogens regulate distinct but overlapping sets of antimicrobial genes. The patterns of genes induced by pathogens do not coincide with any single immune signaling pathway. Thus, even in this simple model system for innate immunity, striking specificity and complexity exist in the immune response. The unique patterns of antimicrobial gene expression observed when C. elegans is exposed to different pathogens or when different immune signaling pathways are perturbed suggest that a large set of yet to be identified pathogen recognition receptors (PRRs) exist in the nematode. These PRRs must interact in a complicated fashion to induce a unique set of antimicrobial genes. We also propose the existence of an “antimicrobial fingerprint,” which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways.

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Genome-wide RNAi screen for synthetic lethal interactions with the C. elegans kinesin-5 homolog BMK-1

Scientific Data ◽

10.1038/sdata.2015.20 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 6

Author(s):

André F. Maia ◽

Marvin E. Tanenbaum ◽

Matilde Galli ◽

Daphne Lelieveld ◽

David A. Egan ◽

...

Keyword(s):

Rnai Screen ◽

Synthetic Lethal ◽

C Elegans ◽

Genome Wide ◽

Synthetic Lethal Interactions

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A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency

Human Molecular Genetics ◽

10.1093/hmg/ddu236 ◽

2014 ◽

Vol 23 (19) ◽

pp. 5123-5132 ◽

Cited By ~ 30

Author(s):

Linda P. O'Reilly ◽

Olivia S. Long ◽

Murat C. Cobanoglu ◽

Joshua A. Benson ◽

Cliff J. Luke ◽

...

Keyword(s):

Drug Targets ◽

Rnai Screen ◽

Potential Drug ◽

C Elegans ◽

Genome Wide ◽

A Genome ◽

Antitrypsin Deficiency ◽

Potential Drug Targets

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Genome-Wide RNAi Screens in C. elegans to Identify Genes Influencing Lifespan and Innate Immunity

Methods in Molecular Biology - High-Throughput RNAi Screening ◽

10.1007/978-1-4939-6337-9_14 ◽

2016 ◽

pp. 171-182 ◽

Cited By ~ 1

Author(s):

Amit Sinha ◽

Robbie Rae

Keyword(s):

Innate Immunity ◽

C Elegans ◽

Genome Wide

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Global transcriptional regulation of innate immunity in C. elegans

10.1101/469817 ◽

2018 ◽

Author(s):

Marissa Fletcher ◽

Erik J. Tillman ◽

Vincent L. Butty ◽

Stuart S. Levine ◽

Dennis H. Kim

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Transcription Factor ◽

Innate Immune Response ◽

Transcriptional Response ◽

Innate Immune ◽

Bzip Transcription Factor ◽

Animal Host ◽

C Elegans ◽

Genome Wide

AbstractThe nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1– ATF-7 signaling reveals global control over the innate immune response to infection through a single transcriptional regulator in a simple animal host.Author SummaryInnate immunity is the first line of defense against invading microbes across metazoans. Caenorhabditis elegans lacks adaptive immunity and is therefore particularly dependent on mounting an innate immune response against pathogens. A major component of this response is the conserved PMK-1/p38 MAPK signaling cascade, the activation of which results in phosphorylation of the bZIP transcription factor ATF-7. Signaling via PMK-1 and ATF-7 causes broad transcriptional changes including the induction of many genes that are predicted to have antimicrobial activity including C-type lectins and lysozymes. In this study, we show that ATF-7 directly regulates the majority of innate immune response genes upon pathogen infection of C. elegans, and demonstrate that many ATF-7 targets function to promote pathogen resistance.

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Casein kinase 1 gamma integrates oxidative stress and innate immune responses

10.21203/rs.3.rs-1185982/v1 ◽

2021 ◽

Author(s):

Long Ma ◽

Yiman Hu ◽

Zhaofa Xu

Keyword(s):

Oxidative Stress ◽

Innate Immunity ◽

Molecular Mechanisms ◽

Casein Kinase ◽

Innate Immune Responses ◽

Casein Kinase 1 ◽

C Elegans ◽

Animal Survival ◽

Immunity Genes ◽

Excess Iodide

Abstract Animals utilize associated pathways to elicit responses to oxidative stress and infection. The molecular mechanisms coordinating these pathways remain unclear. Here, using C. elegans we identified the highly conserved casein kinase 1 gamma CSNK-1 (also known as CK1g or CSNK1G), as a key regulator of these processes. csnk-1 interacted with the bli-3/tsp-15/doxa-1 dual oxidase genes by nonallelic noncomplementation to negatively regulate animal survival in excess iodide, an oxidative stressor. A conserved interaction was detected between DOXA-1 and CSNK-1 and between their human homologs DUOXA2 and CSNK1G2. csnk-1 deficiency resulted in upregulated expression of innate immunity genes and increased animal survival in the pathogenic Pseudomonas aeruginosa PA14. Phosphoproteomic analyses identified decreased phosphorylation of key innate immunity regulators NSY-1 MAPKKK and LIN-45 Raf in csnk-1(lf) mutants. Indeed, NSY-1 and LIN-45 pathways were required for the increased survival of csnk-1-deficient animals in PA14. Further analyses suggest that CSNK-1 and SKN-1 Nrf2 might act in parallel to regulate oxidative stress response. Together, we propose that CSNK-1 CSNK1G plays a novel pivotal role in integrating animal’s responses to oxidative stress and pathogens.

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