Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

ABSTRACT Recently it has been shown that the proinflammatory NF-κB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-κB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-κB pathway requires proteasomal degradation of the inhibitor of NF-κB, IκB. Therefore, we hypothesized that inhibition of proteasomal IκB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-κB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IκB degradation and activation of NF-κB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-κB-dependent expression of antivirus-acting gene products.

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Upon Intranasal Vesicular Stomatitis Virus Infection, Astrocytes in the Olfactory Bulb Are Important Interferon Beta Producers That Protect from Lethal Encephalitis

Journal of Virology ◽

10.1128/jvi.02044-14 ◽

2014 ◽

Vol 89 (5) ◽

pp. 2731-2738 ◽

Cited By ~ 38

Author(s):

Claudia N. Detje ◽

Stefan Lienenklaus ◽

Chintan Chhatbar ◽

Julia Spanier ◽

Chittappen K. Prajeeth ◽

...

Keyword(s):

Olfactory Bulb ◽

Vesicular Stomatitis Virus ◽

Luciferase Expression ◽

Type I ◽

Type I Ifn ◽

Virus Spread ◽

Brain Areas ◽

Reporter Mice ◽

Vesicular Stomatitis ◽

The Brain

ABSTRACTPreviously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (VSV) type I interferon receptor (IFNAR) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. To address whether locally active IFN-β was induced proximally, we studied spatiotemporal conditions of VSV-mediated IFN-β induction. To this end, we performed infection studies with IFN-β reporter mice. One day after intravenous (i.v.) VSV infection, luciferase induction was detected in lymph nodes. Upon i.n. infection, luciferase induction was discovered at similar sites with delayed kinetics, whereas on days 3 and 4 postinfection enhanced luciferase expression additionally was detected in the foreheads of reporter mice. A detailed analysis of cell type-specific IFN-β reporter mice revealed that within the olfactory bulb IFN-β was expressed by neuroectodermal cells, primarily by astrocytes and to a lesser extent by neurons. Importantly, locally induced type I IFN triggered distal parts of the brain as indicated by the analysis of ISRE-eGFP mice which after i.n. VSV infection showed enhanced green fluorescent protein (eGFP) expression throughout the brain. Compared to wild-type mice, IFN-β−/−mice showed increased mortality to i.n. VSV infection, whereas upon i.v. infection no such differences were detected highlighting the biological significance of intracerebrally expressed IFN-β. In conclusion, upon i.n. VSV instillation, IFN-β responses mounted by astrocytes within the olfactory bulb critically contribute to the antiviral defense by stimulating distal IFN-β-negative brain areas and thus arresting virus spread.IMPORTANCEThe central nervous system has long been considered an immune privileged site. More recently, it became evident that specialized immune mechanisms are active within the brain to control pathogens. Previously, we showed that virus, which entered the brain via the olfactory route, was arrested within the olfactory bulb by a type I IFN-dependent mechanism. Since peripheral type I IFN would not readily cross the blood-brain barrier and within the brain thus far no abundant type I IFN responses have been detected, here we addressed from where locally active IFN originated from. We found that upon intranasal VSV instillation, primarily astrocytes, and to a lesser extent neurons, were stimulated within the olfactory bulb to mount IFN-β responses that also activated and protected distal brain areas. Our results are surprising because in other infection models astrocytes have not yet been identified as major type I IFN producers.

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Vesicular Stomatitis Virus M Protein Mutant Stimulates Maturation of Toll-Like Receptor 7 (TLR7)-Positive Dendritic Cells through TLR-Dependent and -Independent Mechanisms

Journal of Virology ◽

10.1128/jvi.02030-08 ◽

2009 ◽

Vol 83 (7) ◽

pp. 2962-2975 ◽

Cited By ~ 33

Author(s):

Maryam Ahmed ◽

Latoya M. Mitchell ◽

Shelby Puckett ◽

Kristina L. Brzoza-Lewis ◽

Douglas S. Lyles ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Vesicular Stomatitis Virus ◽

Knockout Mice ◽

M Protein ◽

Type I ◽

Type I Ifn ◽

Toll Like Receptor ◽

Vesicular Stomatitis ◽

Dc Maturation

ABSTRACT Wild-type (wt) vesicular stomatitis virus (VSV) strains stimulate plasmacytoid dendritic cells (pDC) through Toll-like receptor 7 (TLR7) and its adaptor molecule, MyD88. Granulocyte-macrophage colony-stimulating factor-derived DC (G-DC), which do not express TLR7, are unresponsive to wt VSV due to inhibition of cellular gene expression by the matrix (M) protein. In contrast to its recombinant wt (rwt) counterpart, an M protein mutant of VSV, rM51R-M virus, stimulates maturation of G-DC independently of MyD88. These results suggest that, as in the case of G-DC, rM51R-M virus may stimulate pDC by mechanisms distinct from that by rwt virus. Studies presented here demonstrate that both rwt and rM51R-M viruses induced maturation of TLR7-positive DC derived by culture in the presence of Flt3L (F-DC), with the subsequent expression of type I interferon (IFN). F-DC are a mixture of myeloid (CD11b+) and plasmacytoid (B220+) DC, both of which respond to TLR7 ligands. Separated CD11b+ and B220+ F-DC responded to both rwt and rM51R-M viruses. Both viruses were also defective at inhibiting host gene expression in F-DC, including the expression of genes involved in the antiviral response. The data from F-DC generated from IFN receptor knockout mice demonstrated that the maturation of F-DC induced by rwt virus was dependent on the type I IFN response, while maturation induced by rM51R-M virus was partially dependent on this molecule. Therefore, activation of the type I IFN pathway appears to be important for not only inducing an antiviral response but also for stimulating maturation of F-DC upon virus infection. Importantly, F-DC from TLR7 and MyD88 knockout mice did not undergo maturation in response to rwt virus, while maturation induced by rM51R-M virus was largely independent of both molecules. These results indicate that although both viruses induce F-DC maturation, F-DC detect and respond to rM51R-M virus by means that are distinct from rwt virus. Specifically, this mutant virus appears capable of inducing DC maturation in a wide variety of DC subsets through TLR-dependent and independent mechanisms.

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Matrix Protein Mutant of Vesicular Stomatitis Virus Stimulates Maturation of Myeloid Dendritic Cells

Journal of Virology ◽

10.1128/jvi.80.5.2194-2205.2006 ◽

2006 ◽

Vol 80 (5) ◽

pp. 2194-2205 ◽

Cited By ~ 30

Author(s):

Maryam Ahmed ◽

Kristina L. Brzoza ◽

Elizabeth M. Hiltbold

Keyword(s):

Gene Expression ◽

Vesicular Stomatitis Virus ◽

Host Gene ◽

M Protein ◽

Type I ◽

Type I Ifn ◽

Host Gene Expression ◽

Tumor Immunosurveillance ◽

Vesicular Stomatitis

ABSTRACT Matrix (M) protein mutants of vesicular stomatitis virus have recently been used as oncolytic viruses for tumor therapies and are being developed as vaccine vectors for heterologous antigens. Because dendritic cell (DC) maturation is an important correlate of tumor immunosurveillance and vaccine efficacy, we sought to determine the ability of a recombinant M protein mutant virus (rM51R-M virus) to mature DC in vitro. We have previously shown that rM51R-M virus is defective at inhibiting host gene expression in several cell lines compared to its recombinant wild-type counterpart, rwt virus. Therefore, rM51R-M virus allows the expression of genes involved in antiviral responses, such as the type I interferon (IFN) gene. Our results demonstrate that, in contrast to the rwt virus, rM51R-M virus induced the maturation of myeloid DC (mDC) populations, as indicated by an increase in the surface expression of CD40, CD80, and CD86 as well as the secretion of interleukin-12 (IL-12), IL-6, and type I IFN. In addition, mDC infected with rM51R-M virus effectively activated naïve T cells in vitro, whereas rwt virus-infected mDC were defective in antigen presentation. The inability of rwt virus to induce mDC maturation was correlated with the inhibition of host gene expression in rwt virus-infected cells. Our studies also indicated that the production of costimulatory molecules on mDC by rM51R-M virus was dependent on the type I IFN receptor, while maturation induced by this virus was largely independent of MyD88. These data indicate that rM51R-M virus effectively stimulates the maturation of mDC and has the potential to promote effective T-cell responses to vector-expressed antigens, activate DC at tumor sites during therapy, and aid in tumor immunosurveillance and destruction.

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Photosensitivity and cGAS-dependent type I IFN activation in lupus patients with TREX1 deficiency

10.26226/morressier.61081ff8bc981037240fe447 ◽

2021 ◽

Author(s):

Claudia Günther

Keyword(s):

Type I ◽

Type I Ifn ◽

Dependent Type

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CS16-6. Plasmacytoid Dendritic Cells are infected by Epstein Barr virus and induces TLR- dependent type I IFN production

Cytokine ◽

10.1016/j.cyto.2011.07.411 ◽

2011 ◽

Vol 56 (1) ◽

pp. 106

Author(s):

Martina Severa ◽

Elena Giacomini ◽

Eleni Anastasiadou ◽

Valerie Gafa ◽

Fabiana Rizzo ◽

...

Keyword(s):

Dendritic Cells ◽

Epstein Barr Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Type I Ifn ◽

Barr Virus ◽

Epstein Barr ◽

Dependent Type

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Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

Journal of Virology ◽

10.1128/jvi.00757-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7944-7954 ◽

Cited By ~ 17

Author(s):

Marlena M. Westcott ◽

Jingfang Liu ◽

Karishma Rajani ◽

Ralph D'Agostino ◽

Douglas S. Lyles ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Cancer Cells ◽

Tumor Cells ◽

Vesicular Stomatitis Virus ◽

Oncolytic Viruses ◽

Type I ◽

Normal Cells ◽

Vesicular Stomatitis

ABSTRACTOncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.

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Prophylaxis against a Melanesian variant of human T-lymphotropic virus type I (HTLV-I) in rabbits using HTLV-I immune globulin from asymptomatically infected Japanese carriers

Blood ◽

10.1182/blood.v82.12.3664.3664 ◽

1993 ◽

Vol 82 (12) ◽

pp. 3664-3667 ◽

Cited By ~ 6

Author(s):

Y Tanaka ◽

K Ishii ◽

T Sawada ◽

Y Ohtsuki ◽

H Hoshino ◽

...

Keyword(s):

Vesicular Stomatitis Virus ◽

Virus Type ◽

Neutralizing Antibody ◽

Type I ◽

Chain Reaction ◽

T Lymphotropic Virus ◽

Molecular Variants ◽

Vesicular Stomatitis ◽

Polymerase Chain ◽

Contaminated Blood

Abstract Molecular variants of human T-lymphotropic virus type I (HTLV-I), which diverge significantly from the so-called cosmopolitan prototypes, have been discovered in Melanesia. In this study, HTLV-I IgG (I-IgG) prepared from seropositive healthy Japanese carriers was evaluated for its protective effect against a Melanesian isolate, HTLV-IMEL5, in rabbits. Normal IgG (N-IgG) prepared from seronegative healthy Japanese was used as control. Both preparations contained 50 mg/mL of IgG and I- IgG had a high neutralizing antibody titer, as determined by vesicular stomatitis virus--HTLV-I pseudotype assay. Of four experimental groups (A, B, C, and D), each with three rabbits, groups A and B were infused with 10 mL of N-IgG and I-IgG, respectively, and animals were challenged immediately by transfusion of 5 mL of blood from a rabbit infected with HTLV-IMEL5. Animals in groups C and D were immunized with 10 mL of I-IgG 24 and 48 hours, respectively, after being transfused with 5 mL of blood from the virus-infected rabbit. HTLV-I infection, as determined by seroconversion and verified by polymerase chain reaction, occurred in all rabbits in groups A and D after 2 to 6 weeks, but in none of the animals in groups B and C. These data indicate that I-IgG is protective against HTLV-IMEL5 infection when administered before or within 24 hours of transfusion with virus-contaminated blood. Moreover, our study shows that the neutralizing domains of the so-called cosmopolitan and Melanesian strains of HTLV-I are functionally indistinguishable.

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