M27 expressed by cytomegalovirus counteracts effective type I interferon induction of myeloid cells but not of plasmacytoid dendritic cells

• Published in: Journal of virology 2014-12, Vol.88 (23), p.13638-13650
• Main Authors: Döring, Marius, Lessin, Irina, Frenz, Theresa, Spanier, Julia, Kessler, Annett, Tegtmeyer, Pia, Dağ, Franziska, Thiel, Nadine, Trilling, Mirko, Lienenklaus, Stefan, Weiss, Siegfried, Scheu, Stefanie, Messerle, Martin, Cicin-Sain, Luka, Hengel, Hartmut, Kalinke, Ulrich
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Dendritic Cells - immunology; Human cytomegalovirus; Immune Evasion; Interferon Type I - antagonists & inhibitors; Interferon Type I - immunology; Mice, Inbred C57BL; Murine cytomegalovirus; Muromegalovirus - immunology; Myeloid Cells - immunology; Pathogenesis and Immunity; Viral Proteins - immunology
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.00216-14

In healthy individuals, the functional immune system effectively confines human cytomegalovirus (CMV) replication, while viral immune evasion and persistence preclude sterile immunity. Mouse CMV (MCMV) is a well-established model to study the delicate CMV-host balance. Effective control of MCMV infection depends on the induction of protective type I interferon (IFN-I) responses. Nevertheless, it is unclear whether in professional antigen-presenting cell subsets MCMV-encoded evasins inhibit the induction of IFN-I responses. Upon MCMV treatment, enhanced expression of MCMV immediate-early and early proteins was detected in bone marrow cultures of macrophages and myeloid dendritic cells compared with plasmacytoid dendritic cell cultures, whereas plasmacytoid dendritic cells mounted more vigorous IFN-I responses. Experiments with Toll-like receptor (TLR)- and/or RIG-I like helicase (RLH)-deficient cell subsets revealed that upon MCMV treatment of myeloid cells, IFN-I responses were triggered independently of TLR and RLH signaling, whereas in plasmacytoid dendritic cells, IFN-I induction was strictly TLR dependent. Macrophages and myeloid dendritic cells treated with either UV-inactivated MCMV or live MCMV that lacked the STAT2 antagonist M27 mounted significantly higher IFN-I responses than cells treated with live wild-type MCMV. In contrast, plasmacytoid dendritic cells responded similarly to UV-inactivated and live MCMV. These experiments illustrated that M27 not only inhibited IFN-I-mediated receptor signaling, but also evaded the induction of IFN responses in myeloid dendritic cells. Furthermore, we found that additional MCMV-encoded evasins were needed to efficiently shut off IFN-I responses of macrophages, but not of myeloid dendritic cells, thus further elucidating the subtle adjustment of the host-pathogen balance. MCMV may induce IFN-I responses in fibroblasts and epithelial cells, as well as in antigen-presenting cell subsets. We focused on the analysis of IFN-I responses of antigen-presenting cell subsets, including plasmacytoid dendritic cells, myeloid dendritic cells, and macrophages, which are all triggered by MCMV to mount IFN-I responses. Interestingly, myeloid dendritic cells and macrophages, but not plasmacytoid dendritic cells, are readily MCMV infected and support viral gene expression. As expected from previous studies, plasmacytoid dendritic cells sense MCMV Toll-like receptor 9 (TLR9) dependently, whereas in myeloid cells, IFN-I inductio