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Novel Strategies for Targeting Innate Immune Responses to Influenza

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      We previously reported that TLR4 -/- mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist, Eritoran, blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post-infection. Herein, we extend these findings: anti-TLR4- or TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h prior to PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4 -/- mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks HMGB1-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI, (iii) IL-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the anti-viral drug, oseltamivir, were administered starting 4 days post-infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.

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      Most cited references 58

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      The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.

      The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
        • Record: found
        • Abstract: found
        • Article: not found

        Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.

        Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.
          • Record: found
          • Abstract: found
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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.

            Author and article information

            [1 ]Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD, USA
            [2 ]Sigmovir Biosystems, Inc., Rockville, MD, USA
            [3 ]Dept. of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
            [4 ]Pathology Research, University of Maryland, Baltimore, Baltimore, MD, USA
            [5 ]Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
            [6 ]Dept. Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA
            [7 ]Dept. of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, NY, USA
            [8 ]School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
            [9 ]Mucosal Immunology and Biology Research Center, MGH for Children, Boston, MA, USA
            [10 ]Division of Infectious diseases, Univ. of Colorado Denver, Aurora, CO, USA
            [11 ]Eisai, Inc., Andover, MA, USA
            Author notes
            [# ]Corresponding author: Stefanie N. Vogel, Ph.D., Dept. of Microbiology and Immunology, University of Maryland, School of Medicine, 685 W. Baltimore St., Rm. 380, Baltimore, MD 21201 USA svogel@
            Mucosal Immunol
            Mucosal Immunol
            Mucosal immunology
            8 November 2016
            27 January 2016
            September 2016
            29 November 2016
            : 9
            : 5
            : 1173-1182
            26813341 5125448 10.1038/mi.2015.141 NIHMS746175

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