The Tpl2 mutation Sluggish impairs type I IFN production and increases susceptibility to group B streptococcal disease.
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.
Xiao
Nengming
N
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Eidenschenk
Celine
C
Krebs
Philippe
P
Brandl
Katharina
K
Blasius
Amanda L
AL
Xia
Yu
Y
Khovananth
Kevin
K
Smart
Nora G
NG
Beutler
Bruce
B
D000818:Animals; D005038:Ethylnitrosourea; D020022:Genetic Predisposition to Disease; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008088:Listeriosis / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology; D016296:Mutagenesis / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013290:Streptococcal Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000276:immunology*
D007370:Interferon Type I; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D005038:Ethylnitrosourea