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Herpes simplex virus type 1 (HSV-1)-induced apoptosis in human dendritic cells as a result of downregulation of cellular FLICE-inhibitory protein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequences

Herpes simplex virus type 1 (HSV-1) is one of the most frequent and successful human pathogens. It targets immature dendritic cells (iDCs) to interfere with the antiviral immune response. The mechanisms underlying apoptosis of HSV-1-infected iDCs are not fully understood. Previously, we have shown t...

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Main Authors: Kather, Angela (Author) , Raftery, Martin J. (Author) , Devi-Rao, Gayathri (Author) , Lippmann, Juliane (Author) , Giese, Thomas (Author) , Sandri-Goldin, Rozanne M. (Author) , Schönrich, Günther (Author)
Format: Article (Journal)
Language:English
Published: 2010
In: Journal of virology
Year: 2010, Volume: 84, Issue: 2, Pages: 1034-1046
ISSN:1098-5514
DOI:10.1128/JVI.01409-09
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1128/JVI.01409-09
Verlag, lizenzpflichtig, Volltext: https://journals.asm.org/doi/10.1128/JVI.01409-09
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Author Notes:Angela Kather, Martin J. Raftery, Gayathri Devi-Rao, Juliane Lippmann, Thomas Giese, Rozanne M. Sandri-Goldin, and Günther Schönrich
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Summary:Herpes simplex virus type 1 (HSV-1) is one of the most frequent and successful human pathogens. It targets immature dendritic cells (iDCs) to interfere with the antiviral immune response. The mechanisms underlying apoptosis of HSV-1-infected iDCs are not fully understood. Previously, we have shown that HSV-1-induced apoptosis of iDCs is associated with downregulation of the cellular FLICE-inhibitory protein (c-FLIP), a potent inhibitor of caspase-8-mediated apoptosis. In this study, we prove that HSV-1 induces degradation of c-FLIP in a proteasome-independent manner. In addition, by using c-FLIP-specific small interfering RNA (siRNA) we show for the first time that downregulation of c-FLIP expression is sufficient to drive uninfected iDCs into apoptosis, underlining the importance of this molecule for iDC survival. Surprisingly, we also observed virus-induced c-FLIP downregulation in epithelial cells and many other cell types that do not undergo apoptosis after HSV-1 infection. Microarray analyses revealed that HSV-1-encoded latency-associated transcript (LAT) sequences, which can substitute for c-FLIP as an inhibitor of caspase-8-mediated apoptosis, are much less abundant in iDCs as compared to epithelial cells. Finally, iDCs infected with an HSV-1 LAT knockout mutant showed increased apoptosis when compared to iDCs infected with the corresponding wild-type HSV-1. Taken together, our results demonstrate that apoptosis of HSV-1-infected iDCs requires both c-FLIP downregulation and diminished expression of viral LAT.
Item Description:Online veröffentlicht am 11. November 2009
Gesehen am 08.03.2023
Physical Description:Online Resource
ISSN:1098-5514
DOI:10.1128/JVI.01409-09

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