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The pseudorabies virus glycoprotein gE/gI complex suppresses type I interferon production by plasmacytoid dendritic cells

Jochen Lamote (UGent) , Manon Kestens (UGent) , Cliff Van Waesberghe (UGent) , Jonas Delva (UGent) , Steffi De Pelsmaeker (UGent) , Bert Devriendt (UGent) and Herman Favoreel (UGent)
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Abstract
Plasmacytoid dendritic cells (pDC) play a central role in the antiviral immune response, both in the innate response and in shaping the adaptive response, mainly because of their ability to produce massive amounts of type I interferon (TIIFN). Here, we report that cells infected with the live attenuated Bartha vaccine strain of porcine alphaherpesvirus pseudorabies virus (PRV) trigger a dramatically increased TI-IFN response by porcine primary pDC compared to cells infected with wild-type PRV strains (Becker and Kaplan). Since Bartha is one of the relatively few examples of a highly successful alphaherpesvirus vaccine, identification of factors that may contribute to its efficacy may provide insights for the rational design of other alphaherpesvirus vaccines. The Bartha vaccine genome displays several mutations compared to the genome of wild-type PRV strains, including a large deletion in the unique short (US) region, encompassing the glycoprotein E (gE), gI, US9, and US2 genes. Using recombinant PRV Becker strains harboring the entire Bartha US deletion or single mutations in the four affected US genes, we demonstrate that the absence of the viral gE/gI complex contributes to the observed increased IFN- alpha response. Furthermore, we show that the absence of gE leads to an enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in pDC, which correlates with a higher TI-IFN production by pDC. In conclusion, the PRV Bartha vaccine strain triggers strongly increased TI-IFN production by porcine pDC. Our data further indicate that the gE/gI glycoprotein complex suppresses TI-IFN production by pDC, which represents the first alphaherpesvirus factor that suppresses pDC activity. IMPORTANCE: Sveral aphaherpesviruses, including herpes simpex virus, still lack effective vaccines. However, the highly successful Bartha vaccine has contributed substantially to eradication of the porcine alphaherpesvirus pseudorabies virus (PRV) in several countries. The impact of Bartha on the immune response is still poorly understood. Type I interferon (TI-IFN)-producing plasmacytoid dendritic cells (pDC) may play an important role in vaccine development. Here, we show that Bartha elicits a dramatically increased type I interferon (TI-IFN) response in primary porcine pDC compared to wild-type strains. In addition, we found that the gE/gI complex, which is absent in Bartha, inhibits the pDC TI-IFN response. This is the first description of an immune cell type that is differentially affected by Bartha versus wild-type PRV and is the first report describing an alphaherpesvirus protein that inhibits the TI-IFN response by pDC. These data may therefore contribute to the rational design of other alphaherpesvirus vaccines.
Keywords
pseudorabies, herpes, bartha, plasmacytoid dendritic cells, interferon, PORCINE PERIPHERAL-BLOOD, TEGUMENT PROTEIN US2, RAT VISUAL-SYSTEM, HERPES-SIMPLEX, VIRAL GLYCOPROTEINS, TRANSMISSIBLE GASTROENTERITIS, NERVOUS-SYSTEM, DISEASE VIRUS, ALPHA, INFECTION

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MLA
Lamote, Jochen et al. “The Pseudorabies Virus Glycoprotein gE/gI Complex Suppresses Type I Interferon Production by Plasmacytoid Dendritic Cells.” JOURNAL OF VIROLOGY 91.7 (2017): n. pag. Print.
APA
Lamote, J., Kestens, M., Van Waesberghe, C., Delva, J., De Pelsmaeker, S., Devriendt, B., & Favoreel, H. (2017). The pseudorabies virus glycoprotein gE/gI complex suppresses type I interferon production by plasmacytoid dendritic cells. JOURNAL OF VIROLOGY, 91(7).
Chicago author-date
Lamote, Jochen, Manon Kestens, Cliff Van Waesberghe, Jonas Delva, Steffi De Pelsmaeker, Bert Devriendt, and Herman Favoreel. 2017. “The Pseudorabies Virus Glycoprotein gE/gI Complex Suppresses Type I Interferon Production by Plasmacytoid Dendritic Cells.” Journal of Virology 91 (7).
Chicago author-date (all authors)
Lamote, Jochen, Manon Kestens, Cliff Van Waesberghe, Jonas Delva, Steffi De Pelsmaeker, Bert Devriendt, and Herman Favoreel. 2017. “The Pseudorabies Virus Glycoprotein gE/gI Complex Suppresses Type I Interferon Production by Plasmacytoid Dendritic Cells.” Journal of Virology 91 (7).
Vancouver
1.
Lamote J, Kestens M, Van Waesberghe C, Delva J, De Pelsmaeker S, Devriendt B, et al. The pseudorabies virus glycoprotein gE/gI complex suppresses type I interferon production by plasmacytoid dendritic cells. JOURNAL OF VIROLOGY. 2017;91(7).
IEEE
[1]
J. Lamote et al., “The pseudorabies virus glycoprotein gE/gI complex suppresses type I interferon production by plasmacytoid dendritic cells,” JOURNAL OF VIROLOGY, vol. 91, no. 7, 2017.
@article{8521801,
  abstract     = {Plasmacytoid dendritic cells (pDC) play a central role in the antiviral immune response, both in the innate response and in shaping the adaptive response, mainly because of their ability to produce massive amounts of type I interferon (TIIFN). Here, we report that cells infected with the live attenuated Bartha vaccine strain of porcine alphaherpesvirus pseudorabies virus (PRV) trigger a dramatically increased TI-IFN response by porcine primary pDC compared to cells infected with wild-type PRV strains (Becker and Kaplan). Since Bartha is one of the relatively few examples of a highly successful alphaherpesvirus vaccine, identification of factors that may contribute to its efficacy may provide insights for the rational design of other alphaherpesvirus vaccines. The Bartha vaccine genome displays several mutations compared to the genome of wild-type PRV strains, including a large deletion in the unique short (US) region, encompassing the glycoprotein E (gE), gI, US9, and US2 genes. Using recombinant PRV Becker strains harboring the entire Bartha US deletion or single mutations in the four affected US genes, we demonstrate that the absence of the viral gE/gI complex contributes to the observed increased IFN- alpha response. Furthermore, we show that the absence of gE leads to an enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in pDC, which correlates with a higher TI-IFN production by pDC. In conclusion, the PRV Bartha vaccine strain triggers strongly increased TI-IFN production by porcine pDC. Our data further indicate that the gE/gI glycoprotein complex suppresses TI-IFN production by pDC, which represents the first alphaherpesvirus factor that suppresses pDC activity. 
IMPORTANCE: Sveral aphaherpesviruses, including herpes simpex virus, still lack effective vaccines. However, the highly successful Bartha vaccine has contributed substantially to eradication of the porcine alphaherpesvirus pseudorabies virus (PRV) in several countries. The impact of Bartha on the immune response is still poorly understood. Type I interferon (TI-IFN)-producing plasmacytoid dendritic cells (pDC) may play an important role in vaccine development. Here, we show that Bartha elicits a dramatically increased type I interferon (TI-IFN) response in primary porcine pDC compared to wild-type strains. In addition, we found that the gE/gI complex, which is absent in Bartha, inhibits the pDC TI-IFN response. This is the first description of an immune cell type that is differentially affected by Bartha versus wild-type PRV and is the first report describing an alphaherpesvirus protein that inhibits the TI-IFN response by pDC. These data may therefore contribute to the rational design of other alphaherpesvirus vaccines.},
  articleno    = {e02276-16},
  author       = {Lamote, Jochen and Kestens, Manon and Van Waesberghe, Cliff and Delva, Jonas and De Pelsmaeker, Steffi and Devriendt, Bert and Favoreel, Herman},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {pseudorabies,herpes,bartha,plasmacytoid dendritic cells,interferon,PORCINE PERIPHERAL-BLOOD,TEGUMENT PROTEIN US2,RAT VISUAL-SYSTEM,HERPES-SIMPLEX,VIRAL GLYCOPROTEINS,TRANSMISSIBLE GASTROENTERITIS,NERVOUS-SYSTEM,DISEASE VIRUS,ALPHA,INFECTION},
  language     = {eng},
  number       = {7},
  pages        = {12},
  title        = {The pseudorabies virus glycoprotein gE/gI complex suppresses type I interferon production by plasmacytoid dendritic cells},
  url          = {http://dx.doi.org/10.1128/jvi.02276-16},
  volume       = {91},
  year         = {2017},
}

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