某种肠道细菌
TLR2型
免疫系统
生物
细胞生物学
免疫原
化学
生物化学
先天免疫系统
免疫学
抗体
单克隆抗体
肠道菌群
作者
Munhyung Bae,Chelsi D. Cassilly,Xiaoxi Liu,Sung-Moo Park,Betsabeh Khoramian Tusi,Xiangjun Chen,Jae‐Young Kwon,Pavel Filipčík,Andrew S. Bolze,Zehua Liu,Hera Vlamakis,Daniel B. Graham,Sara J. Buhrlage,Ramnik J. Xavier,Jon Clardy
出处
期刊:Nature
[Springer Nature]
日期:2022-07-27
卷期号:608 (7921): 168-173
被引量:124
标识
DOI:10.1038/s41586-022-04985-7
摘要
Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.
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