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Nature. The TLR4 antagonist Eritoran protects mice from lethal influenza infection
[Source: Nature, full text: (LINK). Edited.]
NATURE | LETTER
The TLR4 antagonist Eritoran protects mice from lethal influenza infection
Kari Ann Shirey, Wendy Lai, Alison J. Scott, Michael Lipsky, Pragnesh Mistry, Lioubov M. Pletneva, Christopher L. Karp, Jaclyn McAlees, Theresa L. Gioannini, Jerrold Weiss, Wilbur H. Chen, Robert K. Ernst, Daniel P. Rossignol, Fabian Gusovsky, Jorge C. G. Blanco & Stefanie N. Vogel
Nature (2013) doi:10.1038/nature12118
Received 19 June 2012 - Accepted 22 March 2013 - Published online 01 May 2013
Contributions: K.A.S. and S.N.V. carried out the study design (with advice from J.C.G.B., D.P.R., J.W., R.K.E. and C.L.K.). K.A.S., W.L., J.C.G.B., L.M.P., A.J.S., T.L.G., J.M. and P.M. performed experiments. M.L. performed histological analysis. F.G., W.H.C. and D.P.R. provided crucial reagents and advice. K.A.S. and S.N.V. prepared the manuscript, with input and approval from all other co-authors.
Competing financial interests: With the exception of F.G., none of the authors have a competing interest. F.G. is an employee of Eisai Inc.
Corresponding author: Correspondence to: Stefanie N. Vogel
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NATURE | LETTER
The TLR4 antagonist Eritoran protects mice from lethal influenza infection
Kari Ann Shirey, Wendy Lai, Alison J. Scott, Michael Lipsky, Pragnesh Mistry, Lioubov M. Pletneva, Christopher L. Karp, Jaclyn McAlees, Theresa L. Gioannini, Jerrold Weiss, Wilbur H. Chen, Robert K. Ernst, Daniel P. Rossignol, Fabian Gusovsky, Jorge C. G. Blanco & Stefanie N. Vogel
Nature (2013) doi:10.1038/nature12118
Received 19 June 2012 - Accepted 22 March 2013 - Published online 01 May 2013
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation1. Subsequently, we reported that Tlr4−/− mice are highly refractory to influenza-induced lethality2, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)?a potent, well-tolerated, synthetic TLR4 antagonist3, 4?blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
Author information: Contributions: K.A.S. and S.N.V. carried out the study design (with advice from J.C.G.B., D.P.R., J.W., R.K.E. and C.L.K.). K.A.S., W.L., J.C.G.B., L.M.P., A.J.S., T.L.G., J.M. and P.M. performed experiments. M.L. performed histological analysis. F.G., W.H.C. and D.P.R. provided crucial reagents and advice. K.A.S. and S.N.V. prepared the manuscript, with input and approval from all other co-authors.
Competing financial interests: With the exception of F.G., none of the authors have a competing interest. F.G. is an employee of Eisai Inc.
Corresponding author: Correspondence to: Stefanie N. Vogel
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