PMID- 23471913
OWN - NLM
STAT- MEDLINE
DCOM- 20131029
LR  - 20211021
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 6
IP  - 3
DP  - 2013 May
TI  - Functional analysis of a zebrafish myd88 mutant identifies key transcriptional 
      components of the innate immune system.
PG  - 841-54
LID - 10.1242/dmm.010843 [doi]
AB  - 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-kB 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.
FAU - van der Vaart, Michiel
AU  - van der Vaart M
AD  - Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The 
      Netherlands.
FAU - van Soest, Joost J
AU  - van Soest JJ
FAU - Spaink, Herman P
AU  - Spaink HP
FAU - Meijer, Annemarie H
AU  - Meijer AH
LA  - eng
GR  - WT 077047/Z/05/Z/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130221
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Zebrafish Proteins)
RN  - 12777-81-0 (Flagellin)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Bacterial Infections/genetics/immunology/microbiology/pathology
MH  - Base Sequence
MH  - Disease Susceptibility
MH  - Edwardsiella tarda/drug effects/physiology
MH  - Embryo, Nonmammalian/drug effects/immunology/microbiology/pathology
MH  - Flagellin/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Homozygote
MH  - Humans
MH  - Immunity, Innate/drug effects/*genetics
MH  - Leukocytes/drug effects/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Molecular Sequence Data
MH  - Mutation/*genetics
MH  - Mycobacterium marinum/drug effects/physiology
MH  - Myeloid Differentiation Factor 88/chemistry/*genetics/metabolism
MH  - Phagocytosis/drug effects/immunology
MH  - Poly I-C/pharmacology
MH  - Salmonella typhimurium/drug effects/physiology
MH  - Signal Transduction/drug effects/genetics/immunology
MH  - Survival Analysis
MH  - *Transcription, Genetic/drug effects
MH  - Transcriptome/genetics
MH  - Zebrafish/*genetics/*immunology/microbiology
MH  - Zebrafish Proteins/chemistry/*genetics/metabolism
PMC - PMC3634667
EDAT- 2013/03/09 06:00
MHDA- 2013/10/30 06:00
PMCR- 2013/05/01
CRDT- 2013/03/09 06:00
PHST- 2013/03/09 06:00 [entrez]
PHST- 2013/03/09 06:00 [pubmed]
PHST- 2013/10/30 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - dmm.010843 [pii]
AID - 0060841 [pii]
AID - 10.1242/dmm.010843 [doi]
PST - ppublish
SO  - Dis Model Mech. 2013 May;6(3):841-54. doi: 10.1242/dmm.010843. Epub 2013 Feb 21.