title: M27 expressed by cytomegalovirus counteracts effective type I interferon induction of myeloid cells but not of plasmacytoid dendritic cells.
abstract: 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.
  
  
  OBJECTIVE
  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 induction is entirely TLR and RLH independent. MCMV-encoded M27 does not impair the IFN-I induction of plasmacytoid dendritic cells, while in myeloid dendritic cells, it reduces IFN-I responses. In macrophages, M27 plus other, not yet identified evasins profoundly inhibit the induction of IFN-I responses. Collectively, these results illustrate that MCMV has evolved diverse mechanisms to differentially modulate IFN-I responses in single immune cell subsets.
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Döring
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Lessin
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Frenz
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Kessler
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Tegtmeyer
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Dağ
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Thiel
authors.affiliation: Institute of Virology, Robert-Koch-Haus, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Messerle
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cicin-Sain
authors.affiliation: Institute of Virology, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
authors.affiliation: Institute for Experimental Infection Research, Twincore, Centre for Experimental and Clinical Infection Research, Hannover Medical School, and Helmholtz Centre for Infection Research, Hannover, Germany ulrich.kalinke@twincore.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D057131:Immune Evasion; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D014764:Viral Proteins