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      Regulation of influenza virus replication by Wnt/β-catenin signaling

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          Abstract

          Wnt/β-catenin signaling is an essential pathway in cell cycle control. Dysregulation of the Wnt/β-catenin signaling pathway during viral infection has been reported. In this study, we examined the effect of modulating Wnt/β-catenin signaling during influenza virus infection. The activation of the Wnt/β-catenin pathway by Wnt3a increased influenza virus mRNA and virus production in in vitro in mouse lung epithelial E10 cells and mRNA expresson of influenza virus genes in vivo in the lungs of mice infected with influenza virus A/Puerto Rico/8/34. However, the inhibition of Wnt/β-catenin signaling by iCRT14 reduced virus titer and viral gene expression in human lung epithelial A549 cells and viral replication in primary mouse alveolar epithelial cells infected with different influenza virus strains. Knockdown of β-catenin also reduced viral protein expression and virus production. iCRT14 acts at the early stage of virus replication. Treatment with iCRT14 inhibited the expression of the viral genes (vRNA, cRNA and mRNA) evaluated in this study. The intraperitoneal administration of iCRT14 reduced viral load, improved clinical signs, and partially protected mice from influenza virus infection.

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          Most cited references37

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          Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.

          The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.
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            Ecological and immunological determinants of influenza evolution.

            In pandemic and epidemic forms, influenza causes substantial, sometimes catastrophic, morbidity and mortality. Intense selection from the host immune system drives antigenic change in influenza A and B, resulting in continuous replacement of circulating strains with new variants able to re-infect hosts immune to earlier types. This 'antigenic drift' often requires a new vaccine to be formulated before each annual epidemic. However, given the high transmissibility and mutation rate of influenza, the constancy of genetic diversity within lineages over time is paradoxical. Another enigma is the replacement of existing strains during a global pandemic caused by 'antigenic shift'--the introduction of a new avian influenza A subtype into the human population. Here we explore ecological and immunological factors underlying these patterns using a mathematical model capturing both realistic epidemiological dynamics and viral evolution at the sequence level. By matching model output to phylogenetic patterns seen in sequence data collected through global surveillance, we find that short-lived strain-transcending immunity is essential to restrict viral diversity in the host population and thus to explain key aspects of drift and shift dynamics.
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              Crosstalk between Wnt/β-Catenin and NF-κB Signaling Pathway during Inflammation

              Besides its important role in embryonic development and homeostatic self-renewal in adult tissues, Wnt/β-catenin signaling exerts both anti-inflammatory and proinflammatory functions. This is, at least partially, due to either repressing or enhancing the NF-κB pathway. Similarly, the NF-κB pathway either positively or negatively regulates Wnt/β-catenin signaling. Different components of the two pathways are involved in this crosstalk, forming a complex regulatory network. This review summarizes our current understanding of the molecular mechanisms underlying the cross-regulation between the two pathways and discusses their involvement in inflammation and inflammation-associated diseases such as cancer.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Writing – original draft
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Formal analysis
                Role: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 January 2018
                2018
                : 13
                : 1
                : e0191010
                Affiliations
                [1 ] The Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America
                [2 ] Oklahoma Center for Respiratory and Infectious Diseases, Stillwater, Oklahoma, United States of America
                [3 ] Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, Oklahoma, United States of America
                [4 ] Oklahoma Animal Disease Diagnostic Laboratory, Stillwater, Oklahoma, United States of America
                [5 ] Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                Mayo Clinic Minnesota, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4811-4897
                Article
                PONE-D-17-29570
                10.1371/journal.pone.0191010
                5764324
                29324866
                78b72db1-d402-476a-a195-882d9e0b25d3
                © 2018 More et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 August 2017
                : 27 December 2017
                Page count
                Figures: 8, Tables: 2, Pages: 21
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI121591, HL116876, HL135152 and GM103648
                Award Recipient :
                Funded by: the Oklahoma Center for the Advancement of Science & Technology
                Award Recipient :
                Funded by: the Oklahoma Center for Adult Stem Cell Research
                Award Recipient :
                Funded by: Lundberg-Kienlen endowment fund and seed grants from the Center of Veterinary Health Sciences, Oklahoma State University
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI062629 and GM103648
                Award Recipient :
                Funded by: the Merit Review Program of the Department of Veterans Affairs
                Award Recipient :
                Funded by: the Flight Attendant Medical Research Institute.
                Award Recipient :
                L.L. is supported by NIH grants AI121591, HL116876, HL135152 and GM103648, the Oklahoma Center for the Advancement of Science & Technology, the Oklahoma Center for Adult Stem Cell Research, the Lundberg-Kienlen endowment fund and seed grants from the Center of Veterinary Health Sciences, Oklahoma State University. J.P.M. is supported by NIH grants AI062629 and GM103648, the Merit Review Program of the Department of Veterans Affairs, and the Flight Attendant Medical Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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