title: 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.
authors: Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.
authors: Kari Ann
authors: KA
authors: Shirey
authors: Wendy
authors: W
authors: Lai
authors: Alison J
authors: AJ
authors: Scott
authors: Michael
authors: M
authors: Lipsky
authors: Pragnesh
authors: P
authors: Mistry
authors: Lioubov M
authors: LM
authors: Pletneva
authors: Christopher L
authors: CL
authors: Karp
authors: Jaclyn
authors: J
authors: McAlees
authors: Theresa L
authors: TL
authors: Gioannini
authors: Jerrold
authors: J
authors: Weiss
authors: Wilbur H
authors: WH
authors: Chen
authors: Robert K
authors: RK
authors: Ernst
authors: Daniel P
authors: DP
authors: Rossignol
authors: Fabian
authors: F
authors: Gusovsky
authors: Jorge C G
authors: JC
authors: Blanco
authors: Stefanie N
authors: SN
authors: Vogel
mesh_terms: D055371:Acute Lung Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004187:Disaccharides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000472:pathogenicity*; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D013403:Sugar Phosphates / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004187:Disaccharides; D008024:Ligands; D018950:Lipopolysaccharide Receptors; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D013403:Sugar Phosphates; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C512420:eritoran
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