The TLR4 antagonist Eritoran protects mice from lethal influenza infection

Shirey et al. Nature 497: 498-503, 2013

Speaker: Chung-Tend Wang (王崇騰)                           Time: 14:00~15:00, Nov 6, 2013

Commentator: Dr. Pin Ling (凌斌 老師)                 Place: Room 601

Abstract

Influenza is a major global cause of illness and death, resulting in an estimated three to five million cases of severe influenza illness and 250000 to 500000 deaths annually.¹ Moreover,increasing resistance to existing antiviral therapy, coupled with the need to administer these agents within 2–3 days after infection, limits their usefulness. Thus, there is a critical need for a safe and effective therapeutic adjunct and/or alternative to influenza vaccines and antiviral agents. Previous studies reported that the ensuing cytokine storm, and in particular, interleukin-6 (IL-6), mediated acute lung injury. In addition TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of acute lung injury.² The authors subsequent findings that Tlr4^−/− mice were protected from lethality caused by mouse-adapted influenza virus.³ The authors propose that blocking TLR4 therapeutically would protect against influenza infection. In this study, authors showing that Eritoran, a potent TLR4 antagonist, is highly protective when administered therapeutically to mice infected with a lethal dose of influenza. Remarkably, the authors indeed find that eritoranreduces influenza A-induced lethality, even when given as late as 6 days post-infection, and also reduces lung pathology, clinical symptoms, hypoxemia, lung cytokine induction, and viral titers. Interestingly, eritoran's action is shown to require TLR4, CD14, and TLR2, and evidence is provided that CD14 may play a role in delivery of eritoran to MD2. Eritoran thus reduces TLR4-dependent pathology presumably through blockade of endogenous TLR4-active agonists produced after influenza infection. Interestingly, the authors show that eritoran not only inhibits TLR4-dependent cytokine induction by oxidized phospholipid, but also reduces influenza-induced production of oxidized phospholipid in the lung in vivo. Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.

References

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2.     Imai, Y. et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133, 235–249 (2008).

3.     Nhu, Q. M. et al. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol. 3, 29–39 (2010).