Novel Functions of Tyrosine Kinase 2 in the Antiviral Defense against Murine Cytomegalovirus

Abstract

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-αβ) in the control of MCMV replication, with a prominent role of IFN-β. MCMV infection leads to the activation of STAT1 and STAT2 in an IFN-αβ receptor 1-dependent manner. Consistent with the role of Tyk2 in IFN-αβ 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-αβ-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-αβ stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses.

Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-γ) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State

“…Further, IFN-␤ constitutively expressed prior to any stimulation with IFN-␥ has been shown to be necessary to maintain STAT1 levels for IFN-␣R1 blockage by antibodies, and it has been shown that depletion of IFN-␤ reduces STAT1 levels (25). In agreement with those studies, reduced STAT1 and STAT2 levels have been reported in IFN-␣R1 Ϫ/Ϫ and Tyk2 Ϫ/Ϫ BMDMs (39,75,76). Furthermore, in the study by Zimmermann et al (2005), it was shown that IFN-␣/␤ contributes to an IFN-␥-induced refractory state in MEFs and that MCMV counteracts this mechanism through the virus-encoded factor M27.…”

“…Type I IFNs are known to effectively inhibit MCMV replication in NIH 3T3 cells and BMDMs (26,76). It is noteworthy that in our study we did not observe a prototypic type I response involving antiviral factors such as PKR, RNase L, ISG-15, or oligoadenylate synthetase.…”

The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8+T-Cell Response

“…Conversely, DCs are important in NK cell activation and the initiation of the specific immune response (11). Upon MCMV infection in vivo, antigen-presenting cells such as conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), and macrophages are key producers of type I IFN and other proinflammatory cytokines (1,12,25,48,57). However, pDCs seem to play a central role in mounting a protective type I IFN response (25,57).…”

Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance

“…Mice deficient for Tyk2 (Tyk2 À/À mice) are viable and fertile but were described to have defects in type I IFN, IL12, and also type II IFN (IFNg) signaling (11,12). Tyk2 À/À mice show an increased susceptibility to various pathogens (11,(13)(14)(15) but are resistant against lipopolysaccharide (LPS)-induced endotoxin shock (16). In addition, Tyk2 is a key regulator for Th1/Th2 balance (17).…”