The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease

J Immunol. 2009 Dec 15;183(12):7975-83. doi: 10.4049/jimmunol.0902718.


Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-alpha production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8(Sluggish) mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-alpha and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ethylnitrosourea*
  • Genetic Predisposition to Disease*
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / immunology
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / biosynthesis
  • Listeriosis / genetics
  • Listeriosis / immunology
  • MAP Kinase Kinase Kinases / genetics*
  • MAP Kinase Kinase Kinases / physiology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muromegalovirus / immunology
  • Mutagenesis* / immunology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / physiology
  • RNA Splicing / genetics
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Streptococcal Infections / enzymology*
  • Streptococcal Infections / genetics
  • Streptococcal Infections / immunology*
  • Streptococcus agalactiae / immunology*


  • Interferon Type I
  • Proto-Oncogene Proteins
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse
  • Ethylnitrosourea