The Tpl2 Mutation Sluggish Impairs Type I IFN Production and Increases Susceptibility to Group B Streptococcal Disease1

Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-α 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 Map3k8Sluggish mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-α 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.

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