Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon (IFN)-induced antiviral responses are mediated through a variety of proteins, including the double-stranded RNA-dependent protein kinase PKR. Here we show that fibroblasts derived from PKR(-/-) mice are more permissive for vesicular stomatitis virus (VSV) infection than are wild-type fibroblasts and demonstrate a deficiency in alpha/beta-IFN-mediated protection. We further show that mice lacking PKR are extremely susceptible to intranasal VSV infection, succumbing within days after instillation with as few as 50 infectious viral particles. Again, alpha/beta-IFN was unable to rescue PKR(-/-) mice from VSV infection. Surprisingly, intranasally infected PKR(-/-) mice died not from pathology of the central nervous system but rather from acute infection of the respiratory tract, demonstrating high virus titers in the lungs compared to similarly infected wild-type animals. These results confirm the role of PKR as the major component of IFN-mediated resistance to VSV infection. Since previous reports have shown PKR to be nonessential for survival in animals challenged with encephalomyocarditis virus, influenza virus, and vaccinia virus (N. Abraham et al., J. Biol. Chem. 274:5953-5962, 1999; Y. Yang et al., EMBO J. 14:6095-6106, 1995), our findings serve to highlight the premise that host dependence on the various mediators of IFN-induced antiviral defenses is pathogen specific.
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PMID:The murine double-stranded RNA-dependent protein kinase PKR is required for resistance to vesicular stomatitis virus. 1100 Feb 29

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma herpesvirus) encodes four open reading frames with homology to cellular proteins of interferon regulatory factor (IRF) family. Three of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found, when overexpressed, to down-regulate the transcriptional activity of interferon type I gene promoters in infected cells by interfering with the transactivating activity of cellular IRFs. In this study, we have further characterized vIRF-2 and shown that it is a nuclear protein which is constitutively expressed in HHV-8-positive pleural effusion lymphoma cell lines. Nuclear localization of vIRF-2 was confirmed by in situ detection of ectopically expressed enhanced green fluorescent protein/vIRF-2 fusion protein. We found that the expression of vIRF-2 in HEK293 cells inhibited the antiviral effect of interferon and rescued translation of vesicular stomatitis virus mRNA from interferon-induced translational block. To provide insight into the mechanism of this effect we have demonstrated that vIRF-2 physically interacts with PKR consequently inhibiting autophosphorylation of double-stranded RNA-activated protein kinase (PKR) and blocking phosphorylation of PKR substrates histone 2A and eukaryotic translation initiation factor 2alpha. These results suggest that the latently expressed vIRF-2 has a role in viral mimicry which targets the activity of interferon-induced PKR kinase. By inhibiting the kinase activity of PKR and consequent down-modulation of protein synthesis, HHV-8 has evolved a mechanism by which it can overcome the interferon-mediated antiviral effect. Thus, the anti-interferon functions of vIRF-2 may contribute to the establishment of a chronic or latent infection.
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PMID:Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. 1116 Jul 38

We have recently shown that vesicular stomatitis virus (VSV) exhibits potent oncolytic activity both in vitro and in vivo (S. Balachandran and G. N. Barber, IUBMB Life 50:135-138, 2000). In this study, we further demonstrated, in vivo, the efficacy of VSV antitumor action by showing that tumors that are defective in p53 function or transformed with myc or activated ras are also susceptible to viral cytolysis. The mechanism of viral oncolytic activity involved the induction of multiple caspase-dependent apoptotic pathways was effective in the absence of any significant cytotoxic T-lymphocyte response, and occurred despite normal PKR activity and eIF2alpha phosphorylation. In addition, VSV caused significant inhibition of tumor growth when administered intravenously in immunocompetent hosts. Our data indicate that VSV shows significant promise as an effective oncolytic agent against a wide variety of malignant diseases that harbor a diversity of genetic defects.
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PMID:Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or myc function and involves the induction of apoptosis. 1123 74

The impact of hepatitis C virus NS5A protein mutations on interferon alfa (IFN-alpha) signaling pathway, cell proliferation, and viability is an important issue that is still under debate. We have therefore combined transient and stable expression in a human hepatocytic cell line (Huh7) of 3 full-length NS5A sequences, isolated from patients with or without response to IFN-alpha therapy. Expression of all 3 NS5A-reduced IFN-alpha global antiviral activity on both vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) replication. We did not show, however, an effect of these 3 NS5A proteins on double-stranded RNA-dependent kinase (PKR) expression and activity as well as colocalization and coimmunoprecipitation between NS5A and PKR. We also failed to show an effect of the 3 NS5A mutants tested on cell proliferation and viability. Overall, our results support an important role of NS5A in controlling IFN-alpha antiviral activity; they show, however, that PKR-independent mechanisms are implicated, at least in liver-derived cells.
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PMID:Expression of hepatitis C virus NS5A natural mutants in a hepatocytic cell line inhibits the antiviral effect of interferon in a PKR-independent manner. 1139 46

The IFN-induced double-stranded RNA (dsRNA)-activated protein kinase PKR is one of the key molecules in the antiviral effects of IFN. To clarify the effects of hepatitis C virus nonstructural protein 5A (NS5A) on antiviral activity of IFN, in particular on PKR kinase activity, in mammalian cells, we established inducible NS5A-expressing cell lines derived from human osteosarcoma (Saos-2). The cells expressing NS5A derived from an IFN-resistant clone (NS5A-lb) that interacted with endogenous PKR in vitro, showed a suppressive effect on IFN function as determined by interference with vesicular stomatitis virus (VSV) infection, whereas NS5A (NS5A-2a) from an IFN-sensitive clone did not block the antiviral effect of IFN. A mutant with deletion of the IFN sensitivity determining region (ISDR) in NS5A-1b (NS5A-AISDR) also interacted with PKR and suppressed its activity in vitro. However, neither NS5A-2a nor the C-terminal truncated mutant of NS5A-1b (NS5A-deltaC) blocked PKR activity. These observations confirmed the previous report that the inhibitory effect of NS5A on IFN activity is mediated at least in part by the repression of PKR. In addition, we showed that IFN sensitivity was determined not only by the ISDR but that the involvement of the C-terminal region of NS5A-1b is important for the suppression of PKR activity.
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PMID:Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. 1183

The interferon-induced antiviral state is mediated by interferon-stimulated genes that are upregulated in concert after stimulation by type I interferons. Because so many viruses encode strategies to inactivate the interferon-inducible double-stranded RNA (dsRNA)-dependent protein kinase PKR, this protein is likely to be a major player in antiviral defense. Here we demonstrate the increased susceptibility of PKR-/- animals to vesicular stomatitis virus (VSV) by the intranasal route, but also demonstrate that the protective effects of PKR are mouse strain dependent. We have found the difference between wild-type-BALB/c and 129SvEv animals to be on the order of 5 logs, with high levels of virus present in the lungs of BALB/c but not 129SvEv animals. To evaluate the sensitivity of PKR-/- mice to VSV clearly, the PKR mutation was bred onto the resistant 129SvEv background. The increased sensitivity of PKR-/- mice, compared to PKR+/+ strain-matched controls, is on the order of 10-fold as measured by median lethal dose (LD50). PKR-/- 129 mice support VSV replication in the lung unlike controls. While this result clearly demonstrates an important role for PKR in protection against VSV infection of the lung, it also underlines the importance of other host factors in containing a viral infection.
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PMID:PKR protection against intranasal vesicular stomatitis virus infection is mouse strain dependent. 1195 46

Interferon (IFN)-gamma, is not only a marker of T(H)1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-gamma, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-gamma in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-gamma in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-gamma signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.
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PMID:The role of IFN-gamma in immune responses to viral infections of the central nervous system. 1240 79

RNA viruses are rapidly emerging as extraordinarily promising agents for oncolytic virotherapy. Integral to the lifecycles of all RNA viruses is the formation of double-stranded RNA, which activates a spectrum of cellular defense mechanisms including the activation of PKR and the release of interferon. Tumors are frequently defective in their PKR signaling and interferon response pathways, and therefore provide a relatively permissive substrate for the propagation of RNA viruses. For most of the oncolytic RNA viruses currently under study, tumor specificity is either a natural characteristic of the virus, or a serendipitous consequence of adapting the virus to propagate in human tumor cell lines. Further refinement and optimization of these oncolytic agents can be achieved through virus engineering. This article provides a summary of the current status of oncolytic virotherapy efforts for seven different RNA viruses, namely, mumps, Newcastle disease virus, measles virus, vesicular stomatitis virus, influenza, reovirus, and poliovirus.
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PMID:RNA viruses as virotherapy agents. 1252 35

The double-stranded RNA-dependent protein kinase (PKR) is induced in mouse and human cells on treatment with interferon. In this study, we have cloned and determined the nucleotide sequences of chicken PKR cDNA in various chicken breeds. Chicken PKR was a 550-amino-acid protein as deduced from the cDNA open reading frame (ORF), and there were specific domains (two double-stranded RNA binding domains (DRBDs) and numerous kinase subdomains) characterized in RNA binding proteins and kinase families. Furthermore, it was suggested that chicken PKR was polymorphic. Transfected cell clones expressing chicken PKR mRNA were demonstrated to confer antiviral responses to vesicular stomatitis virus, except for Koshamo type-3 (KS-3). KS-3 PKR, which has an amino acid substitution at position 507 (Arg to Gln), showed amphibious antiviral responses. This specific amino acid substitution was considered to determine the antiviral function of chicken PKR in addition to essential domains as DRBDs and kinase subdomains.
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PMID:Characterization of the chicken PKR: polymorphism of the gene and antiviral activity against vesicular stomatitis virus. 1507 37

The is a double-stranded RNA-activated protein kinase (PKR) has been largely investigated for its key role in viral host defense. Although best characterized by its function in mediating the antiviral and antiproliferative effects of interferon (IFN), PKR is also implicated in transcriptional regulation, cell differentiation, signal transduction, and tumor suppression. However, recent findings identifying PKR as an important effector of apoptosis have led to an increased interest in PKR modulation as an antitumor strategy. PKR can either be up-regulated through direct induction by the transcription factor E2F-1, or it can be activated through direct protein-protein interactions with the melanoma differentiation-associated gene-7 (MDA7, IL-24). Additionally, the intracellular formation of double-stranded RNA by transfection with antisense RNA complementary to tumor-specific RNA sequences can induce PKR activation and apoptosis selective to these tumor cells. The growing application of viral vector-based gene therapies and oncolytic, replicating viruses that must elude viral defense in order to be effective, has also drawn attention to PKR. Oncolytic viruses, like the attenuated herpes simplex virus R3616, the vesicular stomatitis virus, or reovirus, specifically replicate in tumor cells only because the viral host defense in the permissive cells is suppressed. In this article we review the role of PKR as an effector of apoptosis and a target for tumor treatment strategies and discuss the potential of PKR-modifying agents to treat patients with cancer. Targeted gene therapy against cancer can be approached by activation of PKR with the down-regulation of protein synthesis and induction of apoptosis, or by suppression of PKR with the propagation of oncolytic virus. Since the PKR pathway can be modified by many routes, antitumor therapies combining oncolytic virus, gene therapies, and chemotherapy with PKR modifiers are likely to emerge in the near future as therapeutic options in the treatment of patients with cancer.
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PMID:Genetically targeted cancer therapy: tumor destruction by PKR activation. 1517


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