title: Novel strategies for targeting innate immune responses to influenza.
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 before 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 high-mobility group B1 (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) interleukin (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 antiviral 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.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lai
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.|Sigmovir Biosystems, Rockville, Maryland, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Patel
authors.affiliation: Sigmovir Biosystems, Rockville, Maryland, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Pletneva
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kurt-Jones
authors.affiliation: Pathology Research, University of Maryland, Baltimore, Maryland, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lipsky
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Roger
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Calandra
authors.affiliation: Department Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Tracey
authors.affiliation: Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: A G
authors.initials: AG
authors.lastname: Bowie
authors.affiliation: Mucosal Immunology and Biology Research Center, MGH for Children, Boston, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fasano
authors.affiliation: Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Eisai, Andover, Massachusetts, USA.
authors.forename: F
authors.initials: F
authors.lastname: Gusovsky
authors.affiliation: Sigmovir Biosystems, Rockville, Maryland, USA.
authors.forename: J C G
authors.initials: JC
authors.lastname: Blanco
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004187:Disaccharides / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000494:pharmacology*; D053577:Interleukin-1 Receptor Accessory Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009975:Orthomyxoviridae / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology*; D015398:Signal Transduction; D013403:Sugar Phosphates / Q000494:pharmacology*; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D004187:Disaccharides; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C507767:Il1rap protein, mouse; D007074:Immunoglobulin G; D053577:Interleukin-1 Receptor Accessory Protein; D013403:Sugar Phosphates; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053139:Oseltamivir; C512420:eritoran
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