Novel strategies for targeting innate immune responses to influenza

• Published in: Mucosal immunology Vol. 9; no. 5; pp. 1173 - 1182
• Main Authors: Shirey, K A, Lai, W, Patel, M C, Pletneva, L M, Pang, C, Kurt-Jones, E, Lipsky, M, Roger, T, Calandra, T, Tracey, K J, Al-Abed, Y, Bowie, A G, Fasano, A, Dinarello, C A, Gusovsky, F, Blanco, J C G, Vogel, S N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2016; Elsevier Limited
• Subjects: 631/250/1933; 631/250/255/1578; 631/250/262; 692/700/565/251; Acute Lung Injury - drug therapy; Acute Lung Injury - immunology; Acute Lung Injury - mortality; Acute Lung Injury - virology; Allergology; Animals; Antibodies; Antiviral Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Disaccharides - pharmacology; Drug Synergism; Female; Gastroenterology; Gene Expression Regulation; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - genetics; HMGB1 Protein - immunology; Immunity, Innate; Immunoglobulin G - pharmacology; Immunology; Interleukin-1 Receptor Accessory Protein - antagonists & inhibitors; Interleukin-1 Receptor Accessory Protein - genetics; Interleukin-1 Receptor Accessory Protein - immunology; Lung - drug effects; Lung - immunology; Lung - pathology; Lung - virology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Orthomyxoviridae - drug effects; Orthomyxoviridae - growth & development; Orthomyxoviridae - pathogenicity; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - mortality; Orthomyxoviridae Infections - virology; Oseltamivir - pharmacology; Signal Transduction; Sugar Phosphates - pharmacology; Survival Analysis; Toll-Like Receptor 2 - antagonists & inhibitors; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2015.141

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.