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Inhibition of the TRAIL Death Receptor by CMV Reveals Its Importance in NK Cell-Mediated Antiviral Defense


TRAIL death receptors regulate apoptosis and inflammation, and growing evidence suggests their importance in promoting antiviral defenses. Many viruses encode strategies to modulate signaling by TNF family cytokines in order to shape host defenses. Cytomegaloviruses encode many immune modulatory genes, many of which target the TNF family, highlighting their critical role in host antiviral immunity. Here we show that the mouse cytomegalovirus (MCMV) m166 protein restricts cell surface expression of the TRAIL death receptor in infected cells, thus protecting them from TRAIL mediated apoptosis. An MCMV mutant lacking m166 gene expression (MCMV-m166stop) is severely attenuated for replication in vivo, especially in the liver, where a population of immature natural killer (NK) cells resides that express very high levels of TRAIL. These TRAIL-expressing NK cells are critical for antiviral defense, as their depletion restores replication of MCMV-m166stop to wildtype levels. In addition, replication of MCMV-m166stop is normal in TRAIL-DR deficient mice, definitively demonstrating the importance for m166-mediated inhibition of this TNFR in promoting viral replication and subverting host innate defenses.


Vyšlo v časopise: Inhibition of the TRAIL Death Receptor by CMV Reveals Its Importance in NK Cell-Mediated Antiviral Defense. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004268
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004268

Souhrn

TRAIL death receptors regulate apoptosis and inflammation, and growing evidence suggests their importance in promoting antiviral defenses. Many viruses encode strategies to modulate signaling by TNF family cytokines in order to shape host defenses. Cytomegaloviruses encode many immune modulatory genes, many of which target the TNF family, highlighting their critical role in host antiviral immunity. Here we show that the mouse cytomegalovirus (MCMV) m166 protein restricts cell surface expression of the TRAIL death receptor in infected cells, thus protecting them from TRAIL mediated apoptosis. An MCMV mutant lacking m166 gene expression (MCMV-m166stop) is severely attenuated for replication in vivo, especially in the liver, where a population of immature natural killer (NK) cells resides that express very high levels of TRAIL. These TRAIL-expressing NK cells are critical for antiviral defense, as their depletion restores replication of MCMV-m166stop to wildtype levels. In addition, replication of MCMV-m166stop is normal in TRAIL-DR deficient mice, definitively demonstrating the importance for m166-mediated inhibition of this TNFR in promoting viral replication and subverting host innate defenses.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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