Modulation of Innate Immune Signaling Pathways by Herpesviruses

Liu, Qizhi; Rao, Youliang; Tian, Mao; Zhang, Shu; Feng, Pinghui

doi:10.3390/v11060572

Cited by 25 publications

(22 citation statements)

References 173 publications

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“…3.1. The HCMV Tegument Protein UL35 Antagonizes the Type I Interferon Response Downstream of DNA and RNA Cytosolic Recognition Receptors, but Upstream of the IFNAR CMV has evolved multiple strategies to circumvent its detection by PRR, which would otherwise lead to a potent antiviral response mediated by type I IFN and the clearance of infection [13,33,34]. Recently, we identified the MCMV tegument protein M35 as a strong antagonist that shuts down type I IFN signaling downstream of all PRR classes [15].…”

Section: Resultsmentioning

confidence: 99%

“…CMV has evolved multiple strategies to circumvent its detection by PRR, which would otherwise lead to a potent antiviral response mediated by type I IFN and the clearance of infection [ 13 , 33 , 34 ]. Recently, we identified the MCMV tegument protein M35 as a strong antagonist that shuts down type I IFN signaling downstream of all PRR classes [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

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The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

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The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

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“…Herpesviruses are known for the impressive toolbox they have evolved to circumvent the host's immune response. Throughout the lifelong coexistence with their hosts, herpesviruses antagonise the immune response at every level: the signalling pathways downstream of pattern recognition receptors (PRR) (reviewed in Liu et al, 2019;Stempel et al, 2019) and the IFNα/β receptor (IFNAR) (Zimmermann et al, 2005), Natural Killer cell responses (reviewed in De Pelsmaeker et al, 2018), the complement system (reviewed in Stoermer and Morrison, 2011) and the adaptive immune response (reviewed in Smith and Khanna, 2013). However, our understanding of the interplay between herpesviruses and the interferon-stimulated gene (ISG) network is only in its infancy.…”

Section: Introductionmentioning

confidence: 99%

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

et al. 2020

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“…Herpesviruses employ an array of strategies to evade host immune responses and devote a large number of their genes to block the immune response at multiple levels [ 9 , 10 ]. Gene products of herpesviruses are known to subvert several cellular pathways by virtue of their interaction with host proteins [ 6 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Equine Herpesvirus Type 1 Modulates Cytokine and Chemokine Profiles of Mononuclear Cells for Efficient Dissemination to Target Organs

Pavulraj

Kamel

Stephanowitz

et al. 2020

Viruses

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Equine herpesvirus type 1 (EHV-1) causes encephalomyelopathy and abortion, for which cell-associated viremia and subsequent virus transfer to and replication in endothelial cells (EC) are responsible and prerequisites. Viral and cellular molecules responsible for efficient cell-to-cell spread of EHV-1 between peripheral blood mononuclear cells (PBMC) and EC remain unclear. We have generated EHV-1 mutants lacking ORF1, ORF2, and ORF17 genes, either individually or in combination. Mutant viruses were analyzed for their replication properties in cultured equine dermal cells, PBMC infection efficiency, virus-induced changes in the PBMC proteome, and cytokine and chemokine expression profiles. ORF1, ORF2, and ORF17 are not essential for virus replication, but ORF17 deletion resulted in a significant reduction in plaque size. Deletion of ORF2 and ORF17 gene significantly reduced cell-to-cell virus transfer from virus-infected PBMC to EC. EHV-1 infection of PBMC resulted in upregulation of several pathways such as Ras signaling, oxidative phosphorylation, platelet activation and leukocyte transendothelial migration. In contrast, chemokine signaling, RNA degradation and apoptotic pathways were downregulated. Deletion of ORF1, ORF2 and ORF17 modulated chemokine signaling and MAPK pathways in infected PBMC, which may explain the impairment of virus spread between PBMC and EC. The proteomic results were further confirmed by chemokine assays, which showed that virus infection dramatically reduced the cytokine/chemokine release in infected PBMC. This study uncovers cellular proteins and pathways influenced by EHV-1 after PBMC infection and provide an important resource for EHV-1 pathogenesis. EHV-1-immunomodulatory genes could be potential targets for the development of live attenuated vaccines or therapeutics against virus infection.

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Modulation of Innate Immune Signaling Pathways by Herpesviruses

Cited by 25 publications

References 173 publications

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

Equine Herpesvirus Type 1 Modulates Cytokine and Chemokine Profiles of Mononuclear Cells for Efficient Dissemination to Target Organs

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