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首页> 外文期刊>Infection and immunity >Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge
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Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge

机译：合成的Toll-like受体4激动剂刺激对感染性攻击的天生抵抗力。

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A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.
机译：在鼠传染病模型中评估了合成脂质A模拟物的复合家族（称为氨基烷基氨基葡萄糖苷磷酸酯[AGPs]），以抵抗单核细胞增生李斯特菌和流感病毒的攻击。对于 Listeria 模型，静脉注射AGP，然后在24小时后进行静脉细菌攻击。攻击后2天收获脾脏用于CFU计数。对于流感病毒模型，在鼻内/肺内施用AGP 48小时后，通过鼻内/肺内途径用病毒攻击小鼠。攻击后3周每天评估疾病的严重程度。几种类型的AGP对野生型小鼠的流感病毒或 Listeria 攻击提供了强有力的保护，但它们在C3H / HeJ小鼠中却没有活性，表明AGP对通行费样受体4的依赖性（ TLR4）发出保护作用的信号。结构-活性关系研究表明，AGP对先天性免疫效应子的激活主要取决于三个酰基-氧基-酰基残基中二级酰基链的长度，还取决于与糖苷配基相连的官能团的性质。我们得出的结论是，合成TLR4激动剂的使用可快速药理诱导两种不同病原体对传染病的先天性耐药，这种作用是通过TLR4介导的，并且AGP之间的结构差异可对体内激动剂活性产生显着影响。

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