ZFIN ID: ZDB-PUB-130402-15
Functional analysis of a zebrafish myd88 mutant identifies key transcriptional components of the innate immune system
van der Vaart, M., van Soest, J.J., Spaink, H.P., and Meijer, A.H.
Date: 2013
Source: Disease models & mechanisms   6(3): 841-54 (Journal)
Registered Authors: Meijer, Annemarie H., Spaink, Herman P., van der Vaart, Michiel
Keywords: none
Microarrays: GEO:GSE39274
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Bacterial Infections/genetics
  • Bacterial Infections/immunology
  • Bacterial Infections/microbiology
  • Bacterial Infections/pathology
  • Base Sequence
  • Disease Susceptibility
  • Edwardsiella tarda/drug effects
  • Edwardsiella tarda/physiology
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/immunology
  • Embryo, Nonmammalian/microbiology
  • Embryo, Nonmammalian/pathology
  • Flagellin/metabolism
  • Gene Expression Regulation/drug effects
  • Homozygote
  • Humans
  • Immunity, Innate/drug effects
  • Immunity, Innate/genetics*
  • Leukocytes/drug effects
  • Leukocytes/metabolism
  • Lipopolysaccharides/pharmacology
  • Molecular Sequence Data
  • Mutation/genetics*
  • Mycobacterium marinum/drug effects
  • Mycobacterium marinum/physiology
  • Myeloid Differentiation Factor 88/chemistry
  • Myeloid Differentiation Factor 88/genetics*
  • Myeloid Differentiation Factor 88/metabolism
  • Phagocytosis/drug effects
  • Phagocytosis/immunology
  • Poly I-C/pharmacology
  • Salmonella typhimurium/drug effects
  • Salmonella typhimurium/physiology
  • Signal Transduction/drug effects
  • Signal Transduction/genetics
  • Signal Transduction/immunology
  • Survival Analysis
  • Transcription, Genetic*/drug effects
  • Transcriptome/genetics
  • Zebrafish/genetics*
  • Zebrafish/immunology*
  • Zebrafish/microbiology
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 23471913 Full text @ Dis. Model. Mech.
FIGURES
ABSTRACT

Toll-like receptors (TLRs) are an important class of pattern recognition receptors (PRRs) that recognize microbial and danger signals. Their downstream signaling upon ligand binding is vital for initiation of the innate immune response. In human and mammalian models, myeloid differentiation factor 88 (MYD88) is known for its central role as an adaptor molecule in interleukin 1 receptor (IL-1R) and TLR signaling. The zebrafish is increasingly used as a complementary model system for disease research and drug screening. Here, we describe a zebrafish line with a truncated version of MyD88 as the first zebrafish mutant for a TLR signaling component. We show that this immune-compromised mutant has a lower survival rate under standard rearing conditions and is more susceptible to challenge with the acute bacterial pathogens Edwardsiella tarda and Salmonella typhimurium. Microarray and quantitative PCR analysis revealed that expression of genes for transcription factors central to innate immunity (including NF-κB and AP-1) and the pro-inflammatory cytokine Il1b, is dependent on MyD88 signaling during these bacterial infections. Nevertheless, expression of immune genes independent of MyD88 in the myd88 mutant line was sufficient to limit growth of an attenuated S. typhimurium strain. In the case of infection with the chronic bacterial pathogen Mycobacterium marinum, we show that MyD88 signaling has an important protective role during early pathogenesis. During mycobacterial infection, the myd88 mutant shows accelerated formation of granuloma-like aggregates and increased bacterial burden, with associated lower induction of genes central to innate immunity. This zebrafish myd88 mutant will be a valuable tool for further study of the role of IL1R and TLR signaling in the innate immunity processes underlying infectious diseases, inflammatory disorders and cancer.

ADDITIONAL INFORMATION