The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4
The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4
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DOI：
10.1126/science.1138963
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发表时间：
2007-06-15
期刊：
影响因子：
56.9
通讯作者：
Mitchell, Thomas C.
中科院分区：
文献类型：
--
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
细菌细胞壁的组分脂多糖（LPS）的炎性毒性由衔接蛋白髓样分化因子88（MyD 88）和含有Toll-白细胞介素1受体结构域的衔接子诱导干扰素-β（TRIF）驱动，它们一起介导通过内毒素受体Toll样受体4（TLR 4）的信号传导。单磷酰脂质A（MPLA）是LPS的低毒性衍生物，具有有用的免疫刺激特性，其接近监管机构批准用作人疫苗佐剂。我们在这里报道，在小鼠中，MPLA的佐剂功能的低毒性与TRIF信号传导的偏差有关，我们认为这可能是由这种LPS衍生物的促炎活性的主动抑制而不是被动丧失引起的。这一发现可能对未来疫苗佐剂的开发具有重要意义。
The inflammatory toxicity of lipopolysaccharide (LPS), a component of bacterial cell walls, is driven by the adaptor proteins myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta (TRIF), which together mediate signaling by the endotoxin receptor Toll-like receptor 4 (TLR4). Monophosphoryl lipid A (MPLA) is a low-toxicity derivative of LPS with useful immunostimulatory properties, which is nearing regulatory approval for use as a human vaccine adjuvant. We report here that, in mice, the low toxicity of MPLA's adjuvant function is associated with a bias toward TRIF signaling, which we suggest is likely caused by the active suppression, rather than passive loss, of proinflammatory activity of this LPS derivative. This finding may have important implications for the development of future vaccine adjuvants.