Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.
Project Research Center for Fundamental Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.
Angew Chem Int Ed Engl. 2021 Apr 26;60(18):10023-10031. doi: 10.1002/anie.202012374. Epub 2021 Mar 22.
Alcaligenes faecalis is the predominant Gram-negative bacterium inhabiting gut-associated lymphoid tissues, Peyer's patches. We previously reported that an A. faecalis lipopolysaccharide (LPS) acted as a weak agonist for Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2) receptor as well as a potent inducer of IgA without excessive inflammation, thus suggesting that A. faecalis LPS might be used as a safe adjuvant. In this study, we characterized the structure of both the lipooligosaccharide (LOS) and LPS from A. faecalis. We synthesized three lipid A molecules with different degrees of acylation by an efficient route involving the simultaneous introduction of 1- and 4'-phosphates. Hexaacylated A. faecalis lipid A showed moderate agonistic activity towards TLR4-mediated signaling and the ability to elicit a discrete interleukin-6 release in human cell lines and mice. It was thus found to be the active principle of the LOS/LPS and a promising vaccine adjuvant candidate.
粪产碱杆菌是定居于肠相关淋巴组织（派尔集合淋巴结）的主要革兰氏阴性菌。我们之前曾报道，粪产碱杆菌脂多糖（LPS）作为 Toll 样受体 4（TLR4）/髓样分化因子-2（MD-2）受体的弱激动剂以及 IgA 的有效诱导剂而发挥作用，同时不会引起过度炎症，因此提示粪产碱杆菌 LPS 可用作安全佐剂。在这项研究中，我们对粪产碱杆菌的脂寡糖（LOS）和 LPS 的结构进行了表征。我们通过一种有效的方法合成了三种具有不同酰化程度的脂质 A 分子，该方法涉及同时引入 1-和 4′-磷酸基团。六酰化粪产碱杆菌脂质 A 对 TLR4 介导的信号转导具有中等激动活性，并具有在人细胞系和小鼠中引发离散的白细胞介素-6 释放的能力。因此，它被认为是 LOS/LPS 的活性成分和有前途的疫苗佐剂候选物。
