The TLR4 antagonist Eritoran protects mice from lethal influenza infection.
The TLR4 antagonist Eritoran protects mice from lethal influenza infection.
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迫切需要开发替代每年接种的流感疫苗和获得许可用于减轻流感感染的抗病毒剂的替代品。先前的研究报道，由化学或微生物损伤引起的急性肺损伤（ALI）继发于产生宿主衍生的氧化磷脂，其有效地刺激Toll样受体4（TLR 4）依赖性炎症。随后，我们报道了TLR 4 −/−小鼠对流感诱导的致死性高度顽固，并假设TLR 4信号传导的治疗性拮抗作用将保护免受流感诱导的ALI。在本文中，我们报告了治疗性给予一种有效的、耐受性良好的合成TLR 4拮抗剂E5564，其阻断了小鼠流感诱导的致死性，以及肺部病理学、临床症状、细胞因子和氧化磷脂表达，并降低了病毒滴度。CD 14和TLR 2也是阿托莫兰介导的保护所需的，并且CD 14直接结合阿托莫兰并抑制配体与MD 2的结合。因此，阿托洛尔阻断TLR信号传导代表了一种治疗流感相关炎症以及可能的其他感染的新方法。
There is pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury (ALI) caused by chemical or microbial insults is secondary to 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 hypothesized that therapeutic antagonism of TLR4 signaling would protect against influenza-induced ALI. Herein, we report that therapeutic administration of Eritoran (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 titers. 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 signaling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other, infections.
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