Novel strategies for targeting innate immune responses to influenza.

Autor: Shirey KA; Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA., Lai W; Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA., Patel MC; Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.; Sigmovir Biosystems, Rockville, Maryland, USA., Pletneva LM; Sigmovir Biosystems, Rockville, Maryland, USA., Pang C; Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA., Kurt-Jones E; Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA., Lipsky M; Pathology Research, University of Maryland, Baltimore, Maryland, USA., Roger T; Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland., Calandra T; Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland., Tracey KJ; Department Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA., Al-Abed Y; Department of Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York, USA., Bowie AG; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland., Fasano A; Mucosal Immunology and Biology Research Center, MGH for Children, Boston, Massachusetts, USA., Dinarello CA; Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA., Gusovsky F; Eisai, Andover, Massachusetts, USA., Blanco JC; Sigmovir Biosystems, Rockville, Maryland, USA., Vogel SN; Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2016 Sep; Vol. 9 (5), pp. 1173-82. Date of Electronic Publication: 2016 Jan 27.
DOI: 10.1038/mi.2015.141
Abstrakt: 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.
Competing Interests: With the exception of FG, none of the authors have a competing interest. FG is an employee of Eisai Inc.
Databáze: MEDLINE
Externí odkaz: