A Comprehensive View of Regulation of Gene Expression by Double-stranded RNA-mediated Cell Signaling

Geiss, Gary; Jin, Ge; Guo, Jinjiao; Bumgarner, Roger E.; Katze, Michael G.; Sen, Ganes C.

doi:10.1074/jbc.c100137200

Cited by 199 publications

(143 citation statements)

References 22 publications

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“…The relative expression levels of the genes identified in Table 3 Tables 1 and 2). PRG1 IL8 DEFA1 STK17B NPY1R CEACAM8 DEFA4 MS4A3 IL1R2 PBX1 MAFF IMAP1 HIPK2 RNU22 SON CALM1 SSA2 CD69 PRKRIR IGHM PRDX1 XPO1 GZMA GNLY SH2BP1 SSR4 DDX1 DHX15 PTDSS1 +9 -9 8 10 8 10 13 8 10 13 Patient [50,[61][62][63]. Interestingly, when we analyzed the signature patterns of gene expression in the PBMC of 2 SARS patients that received IFN alfacon-1, compared with a patient that did not, we observed a trend of differential gene expression in the IFN-treated patients that was suggestive of antimicrobial activities.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the antiviral effects of interferon-α against a SARS-like coronoavirus infection in vitro

et al. 2006

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Cell Research | www.cell-research.com Antiviral effects of IFN-α against MHV-1 220 npg ORIGINAL ARTICLE IntroductionIn March 2003, a number of laboratories independently reported the isolation and characterization of a novel coronavirus (CoV) from specimens of patients with severe acute respiratory syndrome (SARS) [1,2]. Although an effective therapeutic strategy against SARS has yet to be developed, interferons (IFN) are recognized to play critical roles in host resistance to viral infection [3][4][5][6], thereby implicating them as potential candidates for SARS CoV treatment. IFNs inhibit viral infection by directly interfering with viral replication and by inducing both an innate and adaptive immune response to infection. IFN-αs are effective in the treatment of hepatitis B and C [7,8] and respiratory coronavirus infections unrelated to the Urbani strain of SARS-CoV [9][10][11][12]. , and combinations of 18] are effective in inhibiting SARS-CoV replication in vitro. Moreover, it was reported that macacque monkeys were protected from infection with SARS CoV by treatment with .IFN alfacon-1 (Infergen, Intermune Corp, Brisbane, California), a synthetic IFN-α designed to represent a consensus , has been shown in both cell culture systems [21] and comparative clinical trials [22] to inhibit viral replication more potently than other IFN-αs. Based on these findings, a pilot study to evaluate the potential clinical benefit and safety of IFN alfacon-1 in SARS treatment was conducted by our laboratory. Interferon (IFN)-αs bind to and activate their cognate cell surface receptor to invoke an antiviral response in target cells. Well-described receptor-mediated signaling events result in transcriptional regulation of IFN sensitive genes, effectors of this antiviral response. Results from a pilot study to evaluate the clinical efficacy of IFN-α treatment of SARS patients provided evidence for IFN-inducible resolution of disease. In this report we examined the contribution of IFN-inducible phosphorylation-activation of specific signaling effectors to protection from infection by a SARS-related murine coronavirus, MHV-1. As anticipated, the earliest receptor-activation event, Jak1 phosphorylation, is critical for IFN-inducible protection from MHV-1 infection. Additionally, we provide evidence for the contribution of two kinases, the MAP kinase p38MAPK, and protein kinase C (PKC) d to antiviral protection from MHV-1 infection. Notably, our data suggest that MHV-1 infection, as for the Urbani SARS coronoavirus, inhibits an IFN response, inferred from the lack of activation of pkr and 2'5'-oas, genes associated with mediating the antiviral activities of IFN-αs. To identify potential target genes that are activated downstream of the IFN-inducible signaling effectors we identified, and that mediate protection from coronavirus infection, we examined the gene expression profiles in the peripheral blood mononuclear cells of SARS patients who received IFN treatment. A subset of differentially regulated genes were distinguished with...

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Section: Discussionmentioning

confidence: 99%

Characterization of the antiviral effects of interferon-α against a SARS-like coronoavirus infection in vitro

et al. 2006

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“…Most information available on the broad molecular effects of dsRNA have been obtained in tumoural cell lines [90], and little is known about the effects of dsRNA or actual viral infection on gene regulation by non-or poorly-dividing cells, such as beta cells. It is conceivable that some of the mechanisms that allow one cell type to eradicate a viral infection in a noncytopathic and cytokine-dependent way might cause death in another cell type [79].…”

Section: Discussionmentioning

confidence: 99%

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

et al. 2003

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Aims/hypothesis. Viral infections and local production of IFN-γ might contribute to beta-cell dysfunction/ death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-γ results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC + IFN-γ-effects, we determined the global profile of genes modified by these agents in primary rat beta cells. Methods. FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-γ, PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.Results. Following a 6-or 24-h treatment with IFN-γ, PIC or IFN-γ and PIC, we observed changes in the expression of 51 to 189 genes. IFN-γ modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-γ up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-γ induced a positive feedback on its own signal transduction. PIC + IFN-γ inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression. Conclusion/interpretation. This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA + IFN-γ, two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA + IFN-γ induced beta-cell dysfunction and death. [Diabetologia (2003[Diabetologia ( ) 46:1641[Diabetologia ( -1657

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“…Previous microarray studies have characterized the genomic response to IFN-␣, IFN-␥, and dsRNA. 16,[40][41][42] The ISGs detected in this study were compared with those seen in PBMC from HCV-infected patients treated with IFN-␣. Because the studies employed different arrays with different gene sets, the data are not directly comparable.…”

Section: Discussionmentioning

confidence: 99%

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

et al. 2006

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The mechanism of the interferon-alpha (IFN-␣)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-␣ in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-␣. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours postinoculation, a time when high levels of circulating pegylated IFN-␣ were still present. W orldwide, approximately 170 million people are chronically infected with hepatitis C virus (HCV), which frequently progresses to serious liver disease, including cirrhosis and hepatocellular carcinoma. 1,2 The current therapy involves the combination of pegylated (peg)-interferon alpha (IFN-␣) and ribavirin (reviewed in Feld and Hoofnagle 3 ) and has response rates for sustained viral clearance of approximately 40% to 50% and 80% to 90% for genotypes 1 and 2/3, respectively. 4,5 However, a significant proportion of the population still develops serious disease as a consequence of HCV infection. HCV infection is the leading cause for liver transplantation in the United States 1,2 and liver cancer due to HCV infection is one of the most rapidly increasing types of cancer in the United States. 6 Little is understood regarding the factors leading to successful or failed viral clearance during IFN-␣ therapy. The early kinetics of viral RNA loss from the circulation during IFN-␣ therapy suggests the presence of two phases. Phase I occurs during the first 24 to 48 hours and is presumed to be due to the decrease in secretion of new virions, whereas phase II kinetics vary between individuals, are predictive of the outcome of therapy, and are thought to be a measurement of loss of infected cells. [7][8][9] We 10,11 and others 12 have previously performed gene expression analyses on liver from chimpanzees that experienced acute-resolving or chronic HCV infections. The

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A Comprehensive View of Regulation of Gene Expression by Double-stranded RNA-mediated Cell Signaling

Cited by 199 publications

References 22 publications

Characterization of the antiviral effects of interferon-α against a SARS-like coronoavirus infection in vitro

Characterization of the antiviral effects of interferon-α against a SARS-like coronoavirus infection in vitro

Global profiling of double stranded RNA- and IFN-?-induced genes in rat pancreatic beta cells

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

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