Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control

PLoS Pathog. 2014 Mar 13;10(3):e1004000. doi: 10.1371/journal.ppat.1004000. eCollection 2014 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Blotting, Western
  • CD48 Antigen
  • Cytomegalovirus Infections / immunology*
  • Female
  • Flow Cytometry
  • Immune Evasion / immunology*
  • Immunoprecipitation
  • Killer Cells, Natural / immunology
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • Muromegalovirus / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Proteins / immunology*

Substances

  • Antigens, CD
  • CD48 Antigen
  • Cd48 protein, mouse
  • Viral Proteins

Grants and funding

This study was supported by the Ministerio de Ciencia e Innovación (MICINN, Spain) through grants SAF 2011-25155 (to AA), and SAF 2012-39536 (to PE), and the TransMedRi grant, No. 256686 (FP7-REGPOT-2010-5; to SJ). NPC and DF were supported by a Formación de Profesorado Universitario fellowship and a Juan de la Cierva postdoctoral contract from the MICINN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.