PLoS Pathogens (Aug 2014)

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

  • Shilpi Verma,
  • Andrea Loewendorf,
  • Qiao Wang,
  • Bryan McDonald,
  • Alec Redwood,
  • Chris A Benedict

DOI
https://doi.org/10.1371/journal.ppat.1004268
Journal volume & issue
Vol. 10, no. 8
p. e1004268

Abstract

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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.