Inhibition of the TRAIL death receptor by CMV reveals its importance in NK cell-mediated antiviral defense

PLoS Pathog. 2014 Aug 14;10(8):e1004268. doi: 10.1371/journal.ppat.1004268. eCollection 2014 Aug.

Abstract

TNF-related apoptosis inducing ligand (TRAIL) death receptors (DR) regulate apoptosis and inflammation, but their role in antiviral defense is poorly understood. Cytomegaloviruses (CMV) encode many immune-modulatory genes that shape host immunity, and they utilize multiple strategies to target the TNF-family cytokines. Here we show that the m166 open reading frame (orf) of mouse CMV (MCMV) is strictly required to inhibit expression of TRAIL-DR in infected cells. An MCMV mutant lacking m166 expression (m166stop) is severely compromised for replication in vivo, most notably in the liver, and depleting natural killer (NK) cells, or infecting TRAIL-DR-/- mice, restored MCMV-m166stop replication completely. These results highlight the critical importance for CMV to have evolved a strategy to inhibit TRAIL-DR signaling to thwart NK-mediated defenses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / metabolism
  • Disease Models, Animal
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / immunology
  • Muromegalovirus / metabolism
  • NIH 3T3 Cells
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Proteins / immunology*
  • Viral Proteins / metabolism

Substances

  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Viral Proteins