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The tpl2 mutation sluggish impairs type i ifn production and increases susceptibility to group b streptococcal disease

Academic Article
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Overview

authors

  • Xiao, N. M.
  • Eidenschenk, C.
  • Krebs, P.
  • Brandl, K.
  • Blasius, A. L.
  • Xia, Y.
  • Khovananth, K.
  • Smart, N. G.
  • Beutler, Bruce

publication date

  • 2009

journal

  • Journal of Immunology  Journal

abstract

  • 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.

subject areas

  • Animals
  • Ethylnitrosourea
  • Genetic Predisposition to Disease
  • Herpesviridae Infections
  • Interferon Type I
  • Listeriosis
  • MAP Kinase Kinase Kinases
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muromegalovirus
  • Mutagenesis
  • Proto-Oncogene Proteins
  • RNA Splicing
  • Signal Transduction
  • Streptococcal Infections
  • Streptococcus agalactiae
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.0902718

PubMed ID

  • 19923465
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Additional Document Info

start page

  • 7975

end page

  • 7983

volume

  • 183

issue

  • 12

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