The TLR4 antagonist Eritoran protects mice from lethal influenza infection

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Abstract

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.

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Figure 1: Eritoran treatment protects mice from lethal influenza challenge.
Figure 2: Eritoran treatment inhibits influenza-induced lung pathology and lung function.
Figure 3: Treatment with Eritoran reduces lung viral titres.
Figure 4: Eritoran treatment suppresses influenza-induced cytokine gene expression.
Figure 5: Molecular requirements of Eritoran-induced protection.

Change history

  • 22 May 2013

    A minor change was made to the Fig. 4 legend.

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Acknowledgements

This work was supported by National Institutes of Health grants AI057575 (J.C.G.B.), AI018797 (S.N.V.), AI059372 (J.W.) and NCRR K12-RR-023250 (W.H.C.), VA Merit Award 1I01BX0000949-01A1 (T.L.G.) and Cystic Fibrosis Foundation RDP Center Grant (C.L.K.).

Author information

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.

Correspondence to Stefanie N. Vogel.

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Competing interests

With the exception of F.G., none of the authors have a competing interest. F.G. is an employee of Eisai Inc.

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Shirey, K., Lai, W., Scott, A. et al. The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497, 498–502 (2013). https://doi.org/10.1038/nature12118

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