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  1. Article: Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2.

    Aliyari, Saba R / Ghaffari, Amir Ali / Pernet, Olivier / Parvatiyar, Kislay / Wang, Yao / Gerami, Hoda / Tong, Ann-Jay / Vergnes, Laurent / Takallou, Armin / Zhang, Adel / Wei, Xiaochao / Chilin, Linda D / Wu, Yuntao / Semenkovich, Clay F / Reue, Karen / Smale, Stephen T / Lee, Benhur / Cheng, Genhong

    Acta pharmaceutica Sinica. B

    2022  Volume 12, Issue 4, Page(s) 1624–1635

    Abstract: SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) ... ...

    Abstract SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.
    Language English
    Publishing date 2022-02-28
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2211-3835
    ISSN 2211-3835
    DOI 10.1016/j.apsb.2022.02.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages.

    Iyer, Shankar Subramanian / Ghaffari, Amir Ali / Cheng, Genhong

    Journal of immunology (Baltimore, Md. : 1950)

    2010  Volume 185, Issue 11, Page(s) 6599–6607

    Abstract: IL-10 is a potent anti-inflammatory molecule that regulates excessive production of inflammatory cytokines during an infection or tissue damage. Dysregulation of IL-10 is associated with a number of autoimmune diseases, and so, understanding the ... ...

    Abstract IL-10 is a potent anti-inflammatory molecule that regulates excessive production of inflammatory cytokines during an infection or tissue damage. Dysregulation of IL-10 is associated with a number of autoimmune diseases, and so, understanding the mechanisms by which IL-10 gene expression is regulated remains an important area of study. Macrophages represent a major source of IL-10, which is generated in response to TLR signaling as a feedback mechanism to curtail inflammatory response. In this study, we identify a signaling pathway in murine bone marrow-derived macrophages in which activation of TLR4 by LPS induces the expression of IL-10 through the sequential induction of type I IFNs followed by induction and signaling through IL-27. We demonstrate that IL-27 signaling is required for robust IL-10 induction by LPS and type I IFNs. IL-27 leads directly to transcription of IL-10 through the activation of two required transcription factors, STAT1 and STAT3, which are recruited to the IL-10 promoter. Finally, through systematic functional promoter-reporter analysis, we identify three cis elements within the proximal IL-10 promoter that play an important role in regulating transcription of IL-10 in response to IL-27.
    MeSH term(s) Animals ; Autocrine Communication/genetics ; Autocrine Communication/immunology ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism ; Cell Line ; Interferon Type I/biosynthesis ; Interferon Type I/genetics ; Interleukin-10/genetics ; Interleukin-10/metabolism ; Interleukins/biosynthesis ; Interleukins/genetics ; Interleukins/physiology ; Lipopolysaccharides/pharmacology ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Paracrine Communication/genetics ; Paracrine Communication/immunology ; Promoter Regions, Genetic/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Transcription, Genetic/immunology ; Transcriptional Activation/immunology
    Chemical Substances Il27 protein, mouse ; Interferon Type I ; Interleukins ; Lipopolysaccharides ; Interleukin-10 (130068-27-8)
    Language English
    Publishing date 2010-11-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1002041
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ud II Zs.37: Show issues Location:
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    Zs.MG 28: Show issues

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  3. Article ; Online: Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation.

    Ding, Xianting / Krutzik, Peter O / Ghaffari, Amir Ali / Zhaozhi, Yixiu / Miranda, Daniel / Cheng, Genhong / Ho, Chih-Ming / Nolan, Garry P / Sanchez, David Jesse

    Antiviral research

    2019  Volume 171, Page(s) 104598

    Abstract: As antiviral drug resistance develops and new viruses emerge there is a pressing need to develop strategies to rapidly develop antiviral therapeutics. Here we use phospho-specific flow cytometry to assess perturbations of many different cellular ... ...

    Abstract As antiviral drug resistance develops and new viruses emerge there is a pressing need to develop strategies to rapidly develop antiviral therapeutics. Here we use phospho-specific flow cytometry to assess perturbations of many different cellular signaling pathways during treatment with drug combinations that are highly effective in blocking Herpes simplex virus type 1 (HSV-1) infection. We discovered two antiviral drug combinations act on distinct signaling pathways, either STAT1 or S6 phosphorylation, to block HSV-1 infection. We focused on upregulation of S6 phosphorylation by HSV-1 infection, and our subsequent finding that ribavirin antagonizes this upregulation of S6 phosphorylation. We go on to show that the S6 kinase inhibitor SL0101 blocks HSV-1 replication in vitro and in an in vivo animal model of HSV-1 infection. Overall, we have used an unbiased analysis of cellular signaling pathways during treatment by antiviral drug combinations to discover a novel antiviral drug target against HSV-1 infection. The outcomes of the approach we present highlight the importance of analyzing how antiviral drugs modulate cellular and pathogen-induced signaling as a method to discover new drug therapy targets.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Biomarkers ; Cell Line ; Cytokines/metabolism ; Disease Models, Animal ; Drug Discovery ; Herpes Simplex/drug therapy ; Herpes Simplex/metabolism ; Herpes Simplex/virology ; Herpesvirus 1, Human/physiology ; Host-Pathogen Interactions ; Humans ; Mice ; Ribavirin/pharmacology ; Ribosomal Protein S6 Kinases/metabolism ; Ribosomes/metabolism ; STAT1 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Biomarkers ; Cytokines ; STAT1 Transcription Factor ; Ribavirin (49717AWG6K) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1)
    Keywords covid19
    Language English
    Publishing date 2019-09-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 306628-9
    ISSN 1872-9096 ; 0166-3542
    ISSN (online) 1872-9096
    ISSN 0166-3542
    DOI 10.1016/j.antiviral.2019.104598
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  4. Article ; Online: Poly I:C enhances susceptibility to secondary pulmonary infections by gram-positive bacteria.

    Tian, Xiaoli / Xu, Feng / Lung, Wing Yi / Meyerson, Cherise / Ghaffari, Amir Ali / Cheng, Genhong / Deng, Jane C

    PloS one

    2012  Volume 7, Issue 9, Page(s) e41879

    Abstract: Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether ...

    Abstract Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether the host's response against the viral infection, independent of the injury caused by the virus, results in impairment of antibacterial host defense. Here, we sought to determine whether the induction of an "antiviral" immune state using various viral recognition receptor ligands was sufficient to result in decreased ability to combat common bacterial pathogens of the lung. Using a mouse model, animals were administered polyinosine-polycytidylic acid (poly I:C) or Toll-like 7 ligand (imiquimod or gardiquimod) intranasally, followed by intratracheal challenge with Streptococcus pneumoniae. We found that animals pre-exposed to poly I:C displayed impaired bacterial clearance and increased mortality. Poly I:C-exposed animals also had decreased ability to clear methicillin-resistant Staphylococcus aureus. Furthermore, we showed that activation of Toll-like receptor (TLR)3 and Retinoic acid inducible gene (RIG-I)/Cardif pathways, which recognize viral nucleic acids in the form of dsRNA, both contribute to poly I:C mediated impairment of bacterial clearance. Finally, we determined that poly I:C administration resulted in significant induction of type I interferons (IFNs), whereas the elimination of type I IFN signaling improved clearance and survival following secondary bacterial pneumonia. Collectively, these results indicate that in the lung, poly I:C administration is sufficient to impair pulmonary host defense against clinically important gram-positive bacterial pathogens, which appears to be mediated by type I IFNs.
    MeSH term(s) Aminoquinolines/pharmacology ; Animals ; Antibodies/pharmacology ; Antigens, Viral/administration & dosage ; Antigens, Viral/immunology ; Disease Susceptibility ; Gene Expression Regulation/drug effects ; Imidazoles/pharmacology ; Imiquimod ; Interferon Inducers/pharmacology ; Interferon Type I/genetics ; Interferon Type I/immunology ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Methicillin-Resistant Staphylococcus aureus/immunology ; Mice ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/immunology ; Pneumococcal Infections/genetics ; Pneumococcal Infections/immunology ; Pneumococcal Infections/microbiology ; Pneumococcal Infections/mortality ; Pneumonia, Bacterial/genetics ; Pneumonia, Bacterial/immunology ; Pneumonia, Bacterial/microbiology ; Pneumonia, Bacterial/mortality ; Poly I-C/administration & dosage ; Poly I-C/immunology ; Receptor, Interferon alpha-beta/genetics ; Receptor, Interferon alpha-beta/immunology ; Receptors, Cell Surface ; Signal Transduction/drug effects ; Staphylococcal Infections/genetics ; Staphylococcal Infections/immunology ; Staphylococcal Infections/microbiology ; Staphylococcal Infections/mortality ; Streptococcus pneumoniae/immunology ; Survival Rate ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 3/immunology
    Chemical Substances Aminoquinolines ; Antibodies ; Antigens, Viral ; Imidazoles ; Interferon Inducers ; Interferon Type I ; Membrane Proteins ; Nerve Tissue Proteins ; Receptors, Cell Surface ; Robo3 protein, mouse ; TLR3 protein, mouse ; Toll-Like Receptor 3 ; gardiquimod ; Receptor, Interferon alpha-beta (156986-95-7) ; Poly I-C (O84C90HH2L) ; Imiquimod (P1QW714R7M)
    Language English
    Publishing date 2012-09-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0041879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells.

    Zhang, Zhiqiang / Kim, Taeil / Bao, Musheng / Facchinetti, Valeria / Jung, Sung Yun / Ghaffari, Amir Ali / Qin, Jun / Cheng, Genhong / Liu, Yong-Jun

    Immunity

    2011  Volume 34, Issue 6, Page(s) 866–878

    Abstract: The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and the adaptor molecule TRIF, by isolation and sequencing ... ...

    Abstract The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and the adaptor molecule TRIF, by isolation and sequencing of poly I:C-binding proteins in myeloid dendritic cells (mDCs). Knockdown of each helicase or TRIF by shRNA blocked the ability of mDCs to mount type I interferon (IFN) and cytokine responses to poly I:C, influenza A virus, and reovirus. Although DDX1 bound poly I:C via its Helicase A domain, DHX36 and DDX21 bound the TIR domain of TRIF via their HA2-DUF and PRK domains, respectively. This sensor was localized within the cytosol, independent of the endosomes. Thus, the DDX1-DDX21-DHX36 complex represents a dsRNA sensor that uses the TRIF pathway to activate type I IFN responses in the cytosol of mDCs.
    MeSH term(s) Adaptor Proteins, Vesicular Transport/immunology ; Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Cell Line ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/immunology ; DEAD-box RNA Helicases/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Humans ; Mice ; Protein Binding ; RNA, Double-Stranded/genetics ; Signal Transduction
    Chemical Substances Adaptor Proteins, Vesicular Transport ; RNA, Double-Stranded ; TICAM-1 protein, mouse ; DDX1 protein, mouse (EC 2.7.7.-) ; DDX21 protein, mouse (EC 2.7.7.-) ; Dhx36 protein, mouse (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2011-04-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2011.03.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4227: Show issues Location:
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    Zs.MG 69: Show issues

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