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.

Signaling Lymphocytic Activation Molecule Family Receptor Homologs in New World Monkey Cytomegaloviruses

“…Immunoprecipitations and Western blot analyses were performed as previously described (16). 300.19 and 300.19-HAS1 cells were surface labeled with biotin (Sigma-Aldrich) and lysed.…”

“…Virus genomes might conceivably encode proteins that minimize or block the expression of SLAMF receptors on the surface of infected target cells, in order to avoid or diminish recognition by their counterreceptors expressed in effector immune cells. Two examples of this class of immune modulators have been reported to date, the Vpu protein of HIV-1, which, via downmodulation of SLAMF6, protects infected CD4 ϩ T cells from lysis by NK cells (15), and the m154 protein of murine CMV, which we have recently shown reduces CD48 macrophage surface expression and debilitates antiviral NK-triggered cell responses (16). Additionally, one could envisage that viruses might have captured cellular SLAMF receptors and shaped them to interfere, via various means, with host SLAMF receptor interactions, thus preventing their activities.…”

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

“…Given the strong antiviral potential of NK cells against herpesviruses in particular, it comes as no surprise that several herpesvirus strategies for evading NK cells have been discovered (5). Interestingly, and paradoxically, such evasion strategies have been reported mainly for betaherpesviruses and gammaherpesviruses (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), while only three reports to date have described NK cell evasion strategies for the largest herpesvirus subfamily, the alphaherpesviruses (18)(19)(20).…”

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

“…The significance of the NK cell response against herpesviruses is also reflected by the various mechanisms that these pathogens have evolved to evade or delay it (4). Indeed, for beta-and gammaherpesviruses, a variety of molecular mechanisms avoiding the NK-mediated antiviral activity have been defined (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Remarkably and paradoxically, such mechanisms have remained largely elusive for the alphaherpesviruses (17).…”