title: The inflammatory bowel disease (IBD) susceptibility genes NOD1 and NOD2 have conserved anti-bacterial roles in zebrafish.
abstract: Inflammatory bowel disease (IBD), in the form of Crohn's disease (CD) or ulcerative colitis (UC), is a debilitating chronic immune disorder of the intestine. A complex etiology resulting from dysfunctional interactions between the intestinal immune system and its microflora, influenced by host genetic susceptibility, makes disease modeling challenging. Mutations in NOD2 have the highest disease-specific risk association for CD, and a related gene, NOD1, is associated with UC. NOD1 and NOD2 encode intracellular bacterial sensor proteins acting as innate immune triggers, and represent promising therapeutic targets. The zebrafish has the potential to aid in modeling genetic and environmental aspects of IBD pathogenesis. Here, we report the characterization of the Nod signaling components in the zebrafish larval intestine. The nod1 and nod2 genes are expressed in intestinal epithelial cells and neutrophils together with the Nod signaling pathway genes ripk2, a20, aamp, cd147, centaurin b1, erbin and grim-19. Using a zebrafish embryo Salmonella infection model, morpholino-mediated depletion of Nod1 or Nod2 reduced the ability of embryos to control systemic infection. Depletion of Nod1 or Nod2 decreased expression of dual oxidase in the intestinal epithelium and impaired the ability of larvae to reduce intracellular bacterial burden. This work highlights the potential use of zebrafish larvae in the study of components of IBD pathogenesis.
authors: Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland 1001, New Zealand.
authors: Stefan H
authors: SH
authors: Oehlers
authors: Maria Vega
authors: MV
authors: Flores
authors: Chris J
authors: CJ
authors: Hall
authors: Simon
authors: S
authors: Swift
authors: Kathryn E
authors: KE
authors: Crosier
authors: Philip S
authors: PS
authors: Crosier
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D003001:Cloning, Molecular; D060467:Disease Resistance / Q000235:genetics; D047108:Embryonic Development; D005393:Fish Diseases / Q000196:embryology / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000196:embryology / Q000235:genetics*; D007814:Larva / Q000201:enzymology / Q000235:genetics; D019255:NADPH Oxidases; D009504:Neutrophils / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D019779:Salmonella enterica / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000382:microbiology*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D029961:Zebrafish Proteins; C542712:duox protein, zebrafish; D019255:NADPH Oxidases