title: Contrasting invertebrate immune defense behaviors caused by a single gene, the Caenorhabditis elegans neuropeptide receptor gene npr-1.
abstract: BACKGROUND
  The invertebrate immune system comprises physiological mechanisms, physical barriers and also behavioral responses. It is generally related to the vertebrate innate immune system and widely believed to provide nonspecific defense against pathogens, whereby the response to different pathogen types is usually mediated by distinct signalling cascades. Recent work suggests that invertebrate immune defense can be more specific at least at the phenotypic level. The underlying genetic mechanisms are as yet poorly understood.
  
  
  RESULTS
  We demonstrate in the model invertebrate Caenorhabditis elegans that a single gene, a homolog of the mammalian neuropeptide Y receptor gene, npr-1, mediates contrasting defense phenotypes towards two distinct pathogens, the Gram-positive Bacillus thuringiensis and the Gram-negative Pseudomonas aeruginosa. Our findings are based on combining quantitative trait loci (QTLs) analysis with functional genetic analysis and RNAseq-based transcriptomics. The QTL analysis focused on behavioral immune defense against B. thuringiensis, using recombinant inbred lines (RILs) and introgression lines (ILs). It revealed several defense QTLs, including one on chromosome X comprising the npr-1 gene. The wildtype N2 allele for the latter QTL was associated with reduced defense against B. thuringiensis and thus produced an opposite phenotype to that previously reported for the N2 npr-1 allele against P. aeruginosa. Analysis of npr-1 mutants confirmed these contrasting immune phenotypes for both avoidance behavior and nematode survival. Subsequent transcriptional profiling of C. elegans wildtype and npr-1 mutant suggested that npr-1 mediates defense against both pathogens through p38 MAPK signaling, insulin-like signaling, and C-type lectins. Importantly, increased defense towards P. aeruginosa seems to be additionally influenced through the induction of oxidative stress genes and activation of GATA transcription factors, while the repression of oxidative stress genes combined with activation of Ebox transcription factors appears to enhance susceptibility to B. thuringiensis.
  
  
  CONCLUSIONS
  Our findings highlight the role of a single gene, npr-1, in fine-tuning nematode immune defense, showing the ability of the invertebrate immune system to produce highly specialized and potentially opposing immune responses via single regulatory genes.
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.|Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing, University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany.
authors.forename: Rania
authors.initials: R
authors.lastname: Nakad
authors.affiliation: Laboratory of Nematology, Wageningen University, Wageningen, 6708 PB, The Netherlands.
authors.forename: L Basten
authors.initials: LB
authors.lastname: Snoek
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Wentao
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Sunna
authors.initials: S
authors.lastname: Ellendt
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schneider
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Timm G
authors.initials: TG
authors.lastname: Mohr
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Lone
authors.initials: L
authors.lastname: Rösingh
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Masche
authors.affiliation: Institute for Clinical Molecular Biology, University of Kiel, 24098, Kiel, Germany.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Rosenstiel
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dierking
authors.affiliation: Laboratory of Nematology, Wageningen University, Wageningen, 6708 PB, The Netherlands.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Kammenga
authors.affiliation: Department of Evolutionary Ecology and Genetics, Zoological Institute, University of Kiel, 24098, Kiel, Germany. hschulenburg@zoologie.uni-kiel.de.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Schulenburg
mesh_terms: D000818:Animals; D001413:Bacillus thuringiensis; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics*; D011550:Pseudomonas aeruginosa; D040641:Quantitative Trait Loci; D017476:Receptors, Neuropeptide Y / Q000235:genetics*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D029742:Caenorhabditis elegans Proteins; C468272:NPR-1 protein, C elegans; D017476:Receptors, Neuropeptide Y
keywords: Caenorhabditis elegans; Immune specificity; Innate immunity; Pathogen avoidance behavior; QTL analysis