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.
journal_name
Naturejournal_title
Natureauthors
Shirey KA,Lai W,Scott AJ,Lipsky M,Mistry P,Pletneva LM,Karp CL,McAlees J,Gioannini TL,Weiss J,Chen WH,Ernst RK,Rossignol DP,Gusovsky F,Blanco JC,Vogel SNdoi
10.1038/nature12118subject
Has Abstractpub_date
2013-05-23 00:00:00pages
498-502issue
7450eissn
0028-0836issn
1476-4687pii
nature12118journal_volume
497pub_type
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