Kari Ann Shirey 1 , Wendy Lai 1 , Mira C. Patel 1 , 2 , Lioubov M. Pletneva 2 , Catherine Pang 3 , Evelyn Kurt-Jones 3 , Michael Lipsky 4 , Thierry Roger 5 , Thierry Calandra 5 , Kevin Tracey 6 , Yousef Al-Abed 7 , Andrew G. Bowie 8 , Alessio Fasano 9 , Charles Dinarello 10 , Fabian Gusovsky 11 , Jorge C.G. Blanco 2 , Stefanie N. Vogel 1
27 January 2016
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.