Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus.
We have recently reported that tyrosine kinase 2 (Tyk2)-deficient mice have a selective defect in the in vivo defense against certain viruses. In our current study we show that Tyk2 is essential for the defense against murine CMV (MCMV). In vivo challenges with MCMV revealed impaired clearance of virus from organs and decreased survival of mice in the absence of Tyk2. Our in vitro studies demonstrate that MCMV replicates to dramatically higher titers in Tyk2-deficient macrophages compared with wild-type cells. We show an essential role of type I IFN (IFN-alphabeta) in the control of MCMV replication, with a prominent role of IFN-beta. MCMV infection leads to the activation of STAT1 and STAT2 in an IFN-alphabeta receptor 1-dependent manner. Consistent with the role of Tyk2 in IFN-alphabeta signaling, activation of STAT1 and STAT2 is reduced in Tyk2-deficient cells. However, lack of Tyk2 results in impaired MCMV-mediated gene induction of only a subset of MCMV-induced IFN-alphabeta-responsive genes. Taken together, our data demonstrate a requirement for Tyk2 in the in vitro and in vivo antiviral defense against MCMV infection. In addition to the established role of Tyk2 as an amplifier of Jak/Stat signaling upon IFN-alphabeta stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses.
Strobl
Birgit
B
Institute of Animal Breeding and Genetics, Veterinary University of Vienna, Vienna, Austria. brigit.strobl@i122server.vu-wien.ac.at
Bubic
Ivan
I
Bruns
Ute
U
Steinborn
Ralf
R
Lajko
Robert
R
Kolbe
Thomas
T
Karaghiosoff
Marina
M
Kalinke
Ulrich
U
Jonjic
Stipan
S
Müller
Mathias
M
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000201:enzymology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D053634:TYK2 Kinase; D015533:Transcriptional Activation; D014779:Virus Replication
D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse