Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge
Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge
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DOI：
10.1128/iai.73.5.3044-3052.2005
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发表时间：
2005-05-01
影响因子：
3.1
通讯作者：
Persing, DH
中科院分区：
文献类型：
--
作者：
Cluff, CW;Baldridge, JR;Persing, DH
在鼠类传染病模型中评估了合成脂质 A 模拟物的化合物家族（称为氨烷基氨基葡萄糖胺磷酸盐 [AGP]）对单核细胞增生李斯特氏菌和流感病毒攻击的保护作用。对于李斯特菌模型，静脉注射 AGP，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周内每天评估疾病的严重程度。几种类型的 AGP 在野生型小鼠中提供了针对流感病毒或李斯特菌攻击的强大保护作用，但它们在 C3H/HeJ 小鼠中没有活性，这表明 AGP 的保护作用依赖于 Toll 样受体 4 (TLR4) 信号传导。结构-活性关系研究表明，AGP 对先天免疫效应子的激活主要取决于三个酰基-氧基-酰基残基内的二级酰基链的长度，以及与苷元成分相连的官能团的性质。我们得出的结论是，施用合成的 TLR4 激动剂可以快速药理学诱导对两种不同病原体类别的感染攻击的先天抵抗力，这种作用是通过 TLR4 介导的，并且 AGP 之间的结构差异可能对体内激动剂活性产生巨大影响。
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.