Cytokines Produced in Response to Varicella-Zoster Virus Infection of ARPE-19 Cells Stimulate Lymphocyte Chemotaxis

Graybill, Chiharu; Claypool, David J.; Brinton, John T.; Levin, Myron J.; Lee, Katherine S

doi:10.1093/infdis/jix426

Cited by 7 publications

(9 citation statements)

References 42 publications

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“…Our findings showed that treatment with 0.2 ng/ml of IFN-␥ reduced intracellular VZV yields less than 2-fold compared to those of untreated cells. Since the levels of IFN-␥ in the supernatant were reduced by VZV infection in both ARPE-19 and MeWo cells compared to those of uninfected cells, and were less than 10 pg/ml (40), IFN-␥ produced in response to VZV infection is not sufficient to inhibit VZV replication.…”

Section: Discussionmentioning

confidence: 93%

“…A cytokine profile of ARPE-19 and MeWo cells in response to VZV (ROka strain) infection showed that VZV-infected ARPE-19 cells secreted high levels of CCL2/monocyte chemoattractant protein 1 (MCP-1), CXCL8/interleukin 8 (IL-8), IL-6, and IL-10 and low levels of IL-2, IL-4, IL-13, and tumor necrosis factor alpha (TNF-␣) (40). The only cytokine induced by VZV infection in MeWo cells was IL-10 (42).…”

Section: Discussionmentioning

confidence: 99%

“…Our findings showed that the titers of VZV (AV92-3:L strain) produced by ARPE-19 cells were slightly higher than those of MRC-5 cells. However, VZV (ROka strain) was able to replicate more efficiently in MRC-5 cells than in ARPE-19 cells (40). VZV-infected ARPE-19 cells exhibited reduced IE62 expression and virus titers compared to those in infected MRC-5 cells (40).…”

Section: Discussionmentioning

confidence: 99%

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Interferon Gamma Inhibits Varicella-Zoster Virus Replication in a Cell Line-Dependent Manner

Shakya

O’Callaghan

Kim

2019

J Virol

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The major immediate early 62 (IE62) protein of varicella-zoster virus (VZV) is delivered to newly infected cell nuclei, where it initiates VZV replication by transactivating viral immediate early (IE), early (E), and late (L) genes. Interferon gamma (IFN-γ) is a potent cytokine produced following primary VZV infection. Furthermore, VZV reactivation correlates with a decline in IFN-γ-producing immune cells. Our results showed that treatment with 20 ng/ml of IFN-γ completely reduced intracellular VZV yield in A549 lung epithelial cells, MRC-5 lung fibroblasts, and ARPE-19 retinal epithelial cells at 4 days post-VZV infection. However, IFN-γ reduced virus yield only 2-fold in MeWo melanoma cells compared to that of untreated cells. IFN-β significantly inhibited VZV replication in both ARPE-19 and MeWo cells. In luciferase assays with VZV open reading frame 61 (ORF61) promoter reporter plasmid, IFN-γ abrogated the transactivation activity of IE62 by 95%, 97%, and 89% in A549, ARPE-19, and MRC-5 cells, respectively. However, IFN-γ abrogated IE62’s transactivation activity by 16% in MeWo cells, indicating that IFN-γ inhibits VZV replication as well as IE62-mediated transactivation in a cell line-dependent manner. The expression of VZV IE62 and ORF63 suppressed by IFN-γ was restored by JAK1 inhibitor treatment, indicating that the inhibition of VZV replication is mediated by JAK/STAT1 signaling. In the presence of IFN-γ, knockdown of interferon response factor 1 (IRF1) increased VZV replication. Ectopic expression of IRF1 reduced VZV yields 4,000-fold in MRC-5 and ARPE-19 cells but 3-fold in MeWo cells. These results suggest that IFN-γ blocks VZV replication by inhibiting IE62 function in a cell line-dependent manner. IMPORTANCE Our results showed that IFN-γ significantly inhibited VZV replication in a cell line-dependent manner. IFN-γ inhibited VZV gene expression after the immediate early stage of infection and abrogated IE62-mediated transactivation. These results suggest that IFN-γ blocks VZV replication by inhibiting IE62 function in a cell line-dependent manner. Understanding the mechanisms by which IFN-γ plays a role in VZV gene programming may be important in determining the tissue restriction of VZV.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interferon Gamma Inhibits Varicella-Zoster Virus Replication in a Cell Line-Dependent Manner

Shakya

O’Callaghan

Kim

2019

J Virol

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“…This result was of great interest to us because recent evidence points to IL-6 as a keystone immunomodulatory cytokine in both healthy and diseased tissues, including a related report about cultured human retinal cells [16]. …”

mentioning

confidence: 99%

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

Jarosinski

Carpenter

Buckingham

et al. 2018

Open Forum Infectious Diseases

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BackgroundThe infectious cycle of varicella-zoster virus (VZV) after reactivation from the dorsal root ganglia includes replication and assembly of complete enveloped virions in the human skin to cause the characteristic herpes zoster (shingles).MethodsTo pursue studies of innate immunity to VZV infection, we have adapted a fetal skin organ culture model to a human neonatal foreskin explant model.ResultsAbundant expression of VZV IE62, gE, and gC was visualized by confocal microscopy while numerous enveloped virions were observed by electron microscopy in infected skin organ cultures. Microarray experiments demonstrated that the patterns of upregulated transcripts differed between VZV-infected cells and VZV-infected skin explants. One result stood out, namely a >30-fold elevated interleukin (IL)-6 level in the infected skin explant that was not present in the infected monolayer culture. The IL-6 results in the polyermase chain reaction (PCR) assay were reproduced by quantitative PCR testing with newly designed primers. To determine if increased transcription was accompanied by increased IL-6 expression, we quantitated the levels of IL-6 protein in the explant media at increasing intervals after infection. We found a statistically significant increase in IL-6 protein levels secreted into the media from VZV-infected skin explants as compared with mock-infected explants.ConclusionsThe cellular stress response to VZV infection in neonatal skin explants included highly elevated levels of IL-6 transcription and expression. This skin organ model could be adapted to other viruses with a skin tropism, such as herpes simplex virus.

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“…ARN and posterior uveitis represent severe intraocular infections that may be complicated by: retinal detachment, occlusive vasculitis, and loss of vision. VZV infection is the commonest cause of both of these eye in lammatory disorders [411,412]. Studies have shown that the following cytokines are signi icantly elevated during ARN: IL-6, IL-8, IL-10, IL-18, IL-15, MIF, MCP-1, Eotoxin, IP10, sICAM-1, and sVCAM-1 and their levels correlate with disease activity, while low levels of the following cytokines have been encountered: IL-2, IL-4, IL-13, and IFN-α [411,412].…”

Section: Role Of Cytokines In Vzv Infectionsmentioning

confidence: 99%

The beneficial effects of varicella zoster virus

Al-Anazi¹,

Wk²,

Al-Jasser³

2019

J Hematol Clin Res

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Varicella zoster virus behaves differently from other herpes viruses as it differs from them in many aspects. Recently, there has been growing evidence on the benefi cial effects of the virus in immune compromised hosts and these effects are translated into prolongation of survival. The reported benefi cial effects of the virus include: (1) stimulation of bone marrow activity in patients with hematologic malignancies and bone marrow failure syndromes, (2) antitumor effects in various hematologic malignancies and solid tumors, and (3) association with graft versus host disease which has anticancer effects. Additionally, there are several reports on the safety of the live-attenuated even in severely immune suppressed individuals and on the emerging role of the virus in cancer immunotherapy. In this review, the following aspects of the virus will be thoroughly discussed: (1) new data on the genetic background, pathogenesis, vaccination, and new therapeutic modalities; (2) bone marrow microenvironment and hematopoiesis; (3) cells involved in the pathogenesis of the virus such as: mesenchymal stem cells, dendritic cells, natural killer cells, T-cells and mononuclear cells; (4) cellular proteins such as open reading frames, glycoproteins, promyelocytic leukemia protein, chaperons, and SUMOs; (5) extracellular vesicles, exosomes, and micro-RNAs; and (6) signaling pathways, cytokines, and interferons.

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Cytokines Produced in Response to Varicella-Zoster Virus Infection of ARPE-19 Cells Stimulate Lymphocyte Chemotaxis

Cited by 7 publications

References 42 publications

Interferon Gamma Inhibits Varicella-Zoster Virus Replication in a Cell Line-Dependent Manner

Interferon Gamma Inhibits Varicella-Zoster Virus Replication in a Cell Line-Dependent Manner

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

The beneficial effects of varicella zoster virus

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