Simian Virus 5 Is a Poor Inducer of Chemokine Secretion from Human Lung Epithelial Cells: Identification of Viral Mutants That Activate Interleukin-8 Secretion by Distinct Mechanisms

Young, Virginia A.; Parks, Griffith D.

doi:10.1128/jvi.77.12.7124-7130.2003

Cited by 16 publications

(15 citation statements)

References 30 publications

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“…3B). Final levels of IL-6 secretion after high-and low-MOI infections with SV5-flagellin differed ϳ6-fold, which is within the variability typically seen in our experiments with SV5-infected A549 cells (16,46). It is unlikely that this reflects differences in cytopathic effect or virus growth, since these parameters were similar for SV5-GFP and the flagellin-expressing viruses.…”

Section: Intracellular Expression Of Flagellin From Wt Sv5supporting

confidence: 48%

“…As shown in Fig. 3A, infection with SV5-GFP induced very little IL-6 secretion, whereas the P/V-CPIϪ virus induced high levels of IL-6, as shown previously (46). Cells infected with SV5-flagellin responded similarly to those infected with P/V-CPIϪ, and high levels of IL-6 secretion were detected as early as 16 h p.i.. After low-MOI infection, the flagellin-expressing virus induced a level of IL-6 secretion similar to that seen with the P/V-CPIϪ virus and much lower than that seen with parental SV5-GFP (Fig.…”

Section: Intracellular Expression Of Flagellin From Wt Sv5supporting

confidence: 48%

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Engineered Expression of the TLR5 Ligand Flagellin Enhances Paramyxovirus Activation of Human Dendritic Cell Function

Arimilli

Johnson

Clark

et al. 2008

J Virol

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The paramyxovirus simian virus 5 (SV5) is a poor activator of human dendritic cell (DC) maturation pathways in vitro, and infected DC do not upregulate cell surface costimulatory proteins or secretion of immunomodulatory cytokines. We evaluated the hypothesis that activation of SV5-infected DC would be enhanced by engineering SV5 to express a Toll-like-receptor (TLR) ligand. To test this hypothesis, a novel virus was engineered such that the gene encoding an intracellular form of the TLR5 ligand flagellin was expressed from the genome of wild-type (WT) SV5 (SV5-flagellin). Cells infected in vitro with the flagellin-expressing virus released low levels of biologically active flagellin, which was capable of stimulating TLR5 signaling. Infection of human peripheral blood mononuclear cell-derived immature DC with SV5-flagellin resulted in enhanced levels of interleukin-6 (IL-6) and IL-12 compared to infection with DC with the parental virus, WT SV5. In contrast to cytokine induction, the flagellin-expressing virus did not appreciably increase DC surface expression of the costimulatory molecule CD80 or CD86 above the level seen with WT SV5 alone. In mixedculture assays, DC infected with the flagellin-expressing virus were more effective at activating gamma interferon secretion from both CD8؉ and CD4 ؉ allogeneic T cells than DC infected with WT SV5. Our results with SV5-directed intracellular expression of flagellin may be applicable to other vectors or pathogenic viruses where overcoming impairment of DC activation could contribute to the development of safer and more effective vaccines.Dendritic cells (DC) are important professional antigenpresenting cells that are capable of recognizing microbial products and promoting innate and adaptive immune responses (5, 38). Upon sensing viral components, DC are triggered to undergo a conversion from a phenotype termed immature into a form that is capable of activating naïve-T-cell functions, such as proliferation, cytokine secretion, and cytolytic activity (5, 38). These DC activation events include increased cell surface expression of costimulatory molecules, such as CD40, CD80, and CD86, as well as increased capacity to secrete immunomodulatory cytokines, such as interleukin-12 (IL-12), IL-6, and tumor necrosis factor alpha (TNF-␣) (5, 14, 38). As such, the ability of DC to be activated in response to infection has important consequences for development of immunity against viruses. Here we describe engineering the paramyxovirus simian virus 5 (SV5) to be more effective at activating human DC to stimulate T-cell function in vitro.Many viruses are poor activators of DC, with infected immature DC showing only limited production of cytokines or upregulation of costimulatory molecules (28). Examples include herpes simplex virus, cytomegalovirus (CMV), vaccinia virus, measles virus (MeV), influenza virus, Lassa fever virus, poliovirus, and Ebola virus (4,9,17,18,20,36,43). This lack of activation of infected DC can result from virus-induced suppression of signaling pathways. Fo...

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Section: Intracellular Expression Of Flagellin From Wt Sv5supporting

confidence: 48%

Section: Intracellular Expression Of Flagellin From Wt Sv5supporting

confidence: 48%

Engineered Expression of the TLR5 Ligand Flagellin Enhances Paramyxovirus Activation of Human Dendritic Cell Function

Arimilli

Johnson

Clark

et al. 2008

J Virol

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“…In contrast, infection of human epithelial cells with rSV5-P/V-CPI Ϫ resulted in premature and elevated levels of viral RNA and protein compared to infection with WT rSV5, and the P/V mutant produced higher yields than the WT (52). In addition, epithelial cells infected with rSV5-P/V-CPI Ϫ secreted large amounts of IFN and other antiviral cytokines (53,57). The most striking contrast between rSV5-P/V-CPI Ϫ and WT SV5 is seen in the degree of cytopathic effect, since infections of tissue culture cell lines and cultures of primary epithelial cells with rSV5-P/V-CPI Ϫ result in extensive cell death by apoptosis (52,54).…”

mentioning

confidence: 93%

“…Recently, the SV5 V protein has also been shown to play a role in limiting the synthesis phase of the IFN response, as translocation of interferon regulatory factor 3 (IRF3) to the nucleus is blocked following SV5 infection (20,42). The SV5 V protein may also play a role in limiting the induction of some proinflammatory cytokines, since while WT SV5 is a poor inducer of IL-8 and monocyte chemoattractant protein 1 in lung epithelial cells, a recombinant SV5 with mutations in the V protein is a potent activator of these host cell genes (57). Thus, the SV5 V protein plays multiple roles in counteracting host cytokine responses, being involved in blocking of both the IFN induction and signaling pathways (11,20,24).…”

mentioning

confidence: 99%

“…However, in epithelial cells, the rSV5-P/V-CPI Ϫ mutant was shown to have a number of additional unexpected phenotypes that were very different from those of WT rSV5. WT rSV5 blocks IFN signaling (12) and is a poor inducer of IFN as well as other cytokines (11,20,57). In addition, infection with WT rSV5 causes a long-term, noncytopathic infection of human cells in vitro (10,20,52).…”

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confidence: 99%

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A Simian Virus 5 (SV5) P/V Mutant Is Less Cytopathic than Wild-Type SV5 in Human Dendritic Cells and Is a More Effective Activator of Dendritic Cell Maturation and Function

Arimilli

Alexander-Miller

Parks

2006

J Virol

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Human epithelial cells infected with the parainfluenza virus simian virus 5 (SV5) show minimal activation of host cell interferon (IFN), cytokine, and cell death pathways. In contrast, a recombinant SV5 P/V gene mutant (rSV5-P/V-CPI ؊ ) overexpresses viral gene products and is a potent inducer of IFN, proinflammatory cytokines, and apoptosis in these cells. In this study, we have compared the outcomes of wild-type (WT) SV5 and rSV5-P/V-CPI ؊ infections of primary human dendritic cells (DC), important antigen-presenting cells for initiating adaptive immune responses. We have tested the hypothesis that a P/V mutant which activates host antiviral responses will be a more potent inducer of DC maturation and function than WT rSV5, which suppresses host cell responses. Infection of peripheral blood mononuclear cell-derived immature DC with WT rSV5 resulted in high levels of viral protein and progeny virus but very little increase in cell surface costimulatory molecules or secretion of IFN and proinflammatory cytokines. In contrast, immature DC infected with the rSV5-P/V-CPI ؊ mutant produced only low levels of viral protein and progeny virus, but these infected cells were induced to secrete IFN-␣ and other cytokines and showed elevated levels of maturation markers. Unexpectedly, DC infected with WT rSV5 showed extensive cytopathic effects and increased levels of active caspase-3, while infection of DC with the P/V mutant was largely noncytopathic. In mixed-culture assays, WT rSV5-infected DC were impaired in the ability to stimulate proliferation of autologous CD4 ؉ T cells, whereas DC infected with the P/V mutant were very effective at activating T-cell proliferation. The addition of a pancaspase inhibitor to DC infected with WT rSV5 reduced cytopathic effects and resulted in higher surface expression levels of maturation markers. Our finding that the SV5 P/V mutant has both a reduced cytopathic effect in human DC compared to WT SV5 and an enhanced ability to induce DC function has implications for the rational design of novel recombinant paramyxovirus vectors based on engineered mutations in the viral P/V gene.

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Neutrophil infiltration and activation in bronchiolitic airways are independent of viral etiology

Cavallaro¹,

Liang²,

Lawrence³

et al. 2016

Pediatric Pulmonology

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Simian Virus 5 Is a Poor Inducer of Chemokine Secretion from Human Lung Epithelial Cells: Identification of Viral Mutants That Activate Interleukin-8 Secretion by Distinct Mechanisms

Cited by 16 publications

References 30 publications

Engineered Expression of the TLR5 Ligand Flagellin Enhances Paramyxovirus Activation of Human Dendritic Cell Function

Engineered Expression of the TLR5 Ligand Flagellin Enhances Paramyxovirus Activation of Human Dendritic Cell Function

A Simian Virus 5 (SV5) P/V Mutant Is Less Cytopathic than Wild-Type SV5 in Human Dendritic Cells and Is a More Effective Activator of Dendritic Cell Maturation and Function

Neutrophil infiltration and activation in bronchiolitic airways are independent of viral etiology

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