title: Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control.
abstract: Receptors of the signalling lymphocyte-activation molecules (SLAM) family are involved in the functional regulation of a variety of immune cells upon engagement through homotypic or heterotypic interactions amongst them. Here we show that murine cytomegalovirus (MCMV) dampens the surface expression of several SLAM receptors during the course of the infection of macrophages. By screening a panel of MCMV deletion mutants, we identified m154 as an immunoevasin that effectively reduces the cell-surface expression of the SLAM family member CD48, a high-affinity ligand for natural killer (NK) and cytotoxic T cell receptor CD244. m154 is a mucin-like protein, expressed with early kinetics, which can be found at the cell surface of the infected cell. During infection, m154 leads to proteolytic degradation of CD48. This viral protein interferes with the NK cell cytotoxicity triggered by MCMV-infected macrophages. In addition, we demonstrate that an MCMV mutant virus lacking m154 expression results in an attenuated phenotype in vivo, which can be substantially restored after NK cell depletion in mice. This is the first description of a viral gene capable of downregulating CD48. Our novel findings define m154 as an important player in MCMV innate immune regulation.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Zarama
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Pérez-Carmona
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Domènec
authors.initials: D
authors.lastname: Farré
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Tomic
authors.affiliation: Department of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Borst
authors.affiliation: Department of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Messerle
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjic
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Immunology Unit, Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Immunology Unit, Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015153:Blotting, Western; D000071178:CD48 Antigen; D003586:Cytomegalovirus Infections / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D057131:Immune Evasion / Q000276:immunology*; D047468:Immunoprecipitation; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018146:Muromegalovirus / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000071178:CD48 Antigen; C000604066:Cd48 protein, mouse; D014764:Viral Proteins