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The TLR4 antagonist Eritoran protects mice from lethal influenza infection.

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 inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, 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 antagonist-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.
AuthorsKari 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
JournalNature (Nature) Vol. 497 Issue 7450 Pg. 498-502 (May 23 2013) ISSN: 1476-4687 [Electronic] England
PMID23636320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antiviral Agents
  • Cytokines
  • Disaccharides
  • Ligands
  • Lipopolysaccharide Receptors
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • Sugar Phosphates
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • eritoran
Topics
  • Acute Lung Injury (complications, drug therapy, pathology, prevention & control)
  • Animals
  • Antiviral Agents (pharmacology, therapeutic use)
  • Cytokines (genetics, immunology)
  • Disaccharides (metabolism, pharmacology, therapeutic use)
  • Female
  • Influenza A Virus, H1N1 Subtype (drug effects, pathogenicity)
  • Ligands
  • Lipopolysaccharide Receptors (metabolism)
  • Lymphocyte Antigen 96 (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections (drug therapy, immunology, pathology, virology)
  • Sugar Phosphates (metabolism, pharmacology, therapeutic use)
  • Survival Analysis
  • Time Factors
  • Toll-Like Receptor 2 (immunology, metabolism)
  • Toll-Like Receptor 4 (antagonists & inhibitors, immunology)

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