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Novel Strategies for Targeting Innate Immune Responses to Influenza

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      Abstract

      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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        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.
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            Author and article information

            Affiliations
            [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@ 123456som.umaryland.edu
            Journal
            101299742
            35518
            Mucosal Immunol
            Mucosal Immunol
            Mucosal immunology
            1933-0219
            1935-3456
            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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            Immunology

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