Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

Sloan, Derek D.; Jerome, Keith R.

doi:10.1128/jvi.01111-07

Cited by 51 publications

(42 citation statements)

References 76 publications

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“…We sought to identify HSV-1-induced signaling events downstream of VP11/12-Lck interactions. Previous studies have documented that HSV-1 infection activates several host signaling effectors, including p38 (22,33,54,71), JNK (22,33,54,71), Akt (4), and the Akt target mTORC1 (65). Since HSV-induced activation of p38 and JNK has been described for Jurkat T cells (54), we first asked whether activation of these kinases requires VP11/12.…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner

Smiley

2011

J Virol

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We previously showed that the herpes simplex virus 1 (HSV-1) tegument protein VP11/12 activates the lymphocyte-specific Src family kinase (SFK) Lck and is tyrosine phosphorylated in an Lck-dependent manner during T cell infection. We now extend these findings to show that ectopic expression of Lck induces robust tyrosine phosphorylation of VP11/12 in Vero cells, strongly suggesting that VP11/12 participates in an Lckmediated signaling pathway as a substrate of Lck or a kinase activated by Lck. We sought to elucidate signaling events downstream of VP11/12-SFK interactions. SFKs lie upstream of the canonical phosphoinositide 3-kinase (PI3K)-Akt pathway in signaling emanating from immune receptors, growth factor receptors, and polyomavirus middle T antigen. Here, we show that VP11/12 is required for virus-induced activation of PI3K-Akt signaling in HSV-infected Jurkat T cells and primary fibroblasts. VP11/12 interacts with PI3K or PI3K signaling complexes during infection, suggesting that VP11/12 activates PI3K directly. SFK activity is required for tyrosine phosphorylation of VP11/12, VP11/12-PI3K interactions, and Akt activation in infected fibroblasts, suggesting that SFK-dependent phosphorylation of VP11/12 is required for interactions with downstream signaling effectors. Akt controls many biological functions, including cell survival, cell motility, and translation, but it is currently unclear which Akt targets are modulated by VP11/12 during infection. Although the Akt target mTORC1 is activated during HSV-1 infection, VP11/12 is not required for this effect, implying that one or more additional viral proteins regulate this pathway. Further studies are therefore required to determine which Akt targets and associated biological functions are uniquely modulated by VP11/12.

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Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner

Smiley

2011

J Virol

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“…The interaction between alphaherpesviruses and ERK1/2 signaling has been studied extensively for the past years (17)(18)(19)(20)(21)23). This signaling axis controls various fundamental cellular events, making it an attractive target for the virus to subvert the host, promoting viral replication and survival.…”

Section: Discussionmentioning

confidence: 99%

“…Investigating ERK1/2 modulation in T lymphocytes may be of special interest since this signaling pathway is involved in T cell activation, aggregation, and motility (22)(23)(24)(25) and since T lymphocytes may be involved in virus spread and transmission of some alphaherpesviruses. The latter is particularly evident for the Varicellovirus species VZV, whose tropism for T cells contributes to several central aspects of its pathogenesis, including viral dissemination in the body, transmission to skin cells, and spread to new hosts (26)(27)(28).…”

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confidence: 99%

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

Pontes

Devriendt

Favoreel

2015

J Virol

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The interaction between viruses and immune cells of the host may lead to modulation of intracellular signaling pathways and to subsequent changes in cellular behavior that are of benefit for either virus or host. ERK1/2 (extracellular signal regulated kinase 1/2) signaling represents one of the key cellular signaling axes. Here, using wild-type and gE null virus, recombinant gE, and gEtransfected cells, we show that the gE glycoprotein of the porcine Varicellovirus pseudorabies virus (PRV) triggers ERK1/2 phosphorylation in Jurkat T cells and primary porcine T lymphocytes. PRV-induced ERK1/2 signaling resulted in homotypic T cell aggregation and increased motility of T lymphocytes. Our study reveals a new function of the gE glycoprotein of PRV and suggests that PRV, through activation of ERK1/2 signaling, has a substantial impact on T cell behavior. IMPORTANCEHerpesviruses are known to be highly successful in evading the immune system of their hosts, subverting signaling pathways of the host to their own advantage. The ERK1/2 signaling pathway, being involved in many cellular processes, represents a particularly attractive target for viral manipulation. Glycoprotein E (gE) is an important virulence factor of alphaherpesviruses, involved in viral spread. In this study, we show that gE has the previously uncharacterized ability to trigger ERK1/2 phosphorylation in T lymphocytes. We also show that virus-induced ERK1/2 signaling leads to increased migratory behavior of T cells and that migratory T cells can spread the infection to susceptible cells. In conclusion, our results point to a novel function for gE and suggest that virus-induced ERK1/2 activation may trigger PRV-carrying T lymphocytes to migrate and infect other cells susceptible to PRV replication.A lphaherpesviruses constitute the largest subfamily of the herpesviruses. This subfamily contains closely related pathogens, including herpes simplex virus 1 (HSV-1), HSV-2, and varicellazoster virus (VZV) in humans. Another member of the alphaherpesvirus subfamily is the porcine pseudorabies virus (PRV), which is often used as a model to study general features of alphaherpesvirus biology (1).PRV encodes 11 glycoproteins (2) incorporated in the viral envelope, which are embedded in different host membranes of the infected cell, including the plasma membrane. One of these glycoproteins is glycoprotein E (gE), which is important for virulence and viral (neuronal) spread (3-10). For both PRV and HSV-1, there are indications that gE may have a signaling function in immune cells, as it drives signaling-dependent processes like cell surface antigen capping (11-13). However, to date, there are no reports that gE indeed triggers any particular signaling pathway.The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway, controlling many fundamental cellular events, such as cell proliferation, survival, differentiation, migration, apoptosis, and metabolism (14-16). It ma...

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“…Several HSV proteins, such as the ubiquitin ligase ICP0, interact with the IFN pathway. Contact of T cells with HSV-infected cells inhibits and alters T cell signaling via intracellular phosphorylation cascades (86), and ICP47 blocks CD8 + T cell responses by interactions with the transporter associated with antigen processing (TAP), which moves peptides to MHC class I (87). With the knowledge of specific HSV immune evasion mechanisms, it is possible to create replication-competent or -incompetent virus-based vaccines modified to disable inhibitors of innate and acquired immunity.…”

Section: Immune Evasionmentioning

confidence: 99%

HSV-2: in pursuit of a vaccine

Johnston

Koelle²,

Wald³

2011

J. Clin. Invest.

126

111

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Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.

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Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

Cited by 51 publications

References 76 publications

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

HSV-2: in pursuit of a vaccine

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