Bacterial Peptidoglycan Fragments Differentially Regulate Innate Immune Signaling.
Bacterial Peptidoglycan Fragments Differentially Regulate Innate Immune Signaling.
复制标题
细菌肽聚糖片段差异调节先天免疫信号。
DOI：
10.1021/acscentsci.1c00200
复制
发表时间：
2021-04-28
影响因子：
18.2
通讯作者：
Grimes CL
中科院分区：
文献类型：
--
作者：
Bersch KL;DeMeester KE;Zagani R;Chen S;Wodzanowski KA;Liu S;Mashayekh S;Reinecker HC;Grimes CL
人类先天性免疫系统使用细菌肽聚糖（PG）识别元件在分子水平上对病原体和肠道细菌两者作出响应。传统上，已知为胞壁酰二肽（MDP）和N-羟乙酰基MDP（ng-MDP）的合成的和商业上可获得的PG单糖单元已用于探测模式识别受体（例如NOD样受体）的先天免疫激活的机制。然而，细菌PG是一个动态和复杂的结构，具有各种化学修饰和修剪机制，导致产生含dislidamide的元素。这些分子构成免疫刺激筛选的有吸引力的目标，然而，研究是有限的，因为它们的合成的可及性。受肠道微生物嗜酸乳杆菌（Lactobacillus acidophilus）产生的含二糖的化合物的启发，实施了基于PG的二糖配体的稳健且可扩展的化学合成。与单糖PG文库一起，筛选化合物刺激骨髓源性巨噬细胞中促炎基因的能力。这些数据揭示了单糖和二糖PG单位的不同基因诱导模式，表明PG先天免疫信号传导比一个激活因子-一个途径程序更复杂，因为生物学相关片段在不同程度上诱导转录程序。这些双糖分子将作为关键的免疫刺激工具，以更精确地定义专门的先天免疫调节机制，以区分微生物组中的共生细菌和致病细菌。生物启发的肽聚糖片段的合成揭示了复杂的免疫途径激活转录程序，诱导与炎症性肠病相关的基因。
The human innate immune system responds to both pathogen and commensal bacteria at the molecular level using bacterial peptidoglycan (PG) recognition elements. Traditionally, synthetic and commercially accessible PG monosaccharide units known as muramyl dipeptide (MDP) and N-glycolyl MDP (ng-MDP) have been used to probe the mechanism of innate immune activation of pattern recognition receptors, such as NOD-like receptors. However, bacterial PG is a dynamic and complex structure, with various chemical modifications and trimming mechanisms that result in the production of disaccharide-containing elements. These molecules pose as attractive targets for immunostimulatory screening; however, studies are limited because of their synthetic accessibility. Inspired by disaccharide-containing compounds produced from the gut microbe Lactobacillus acidophilus, a robust and scalable chemical synthesis of PG-based disaccharide ligands was implemented. Together with a monosaccharide PG library, compounds were screened for their ability to stimulate proinflammatory genes in bone-marrow-derived macrophages. The data reveal distinct gene induction patterns for monosaccharide and disaccharide PG units, suggesting that PG innate immune signaling is more complex than a one activator–one pathway program, as biologically relevant fragments induce transcriptional programs to different degrees. These disaccharide molecules will serve as critical immunostimulatory tools to more precisely define specialized innate immune regulatory mechanisms that distinguish between commensal and pathogenic bacteria residing in the microbiome. Synthesis of biologically inspired peptidoglycan fragments reveals a complex immune pathway activating transcriptional programs that induce genes associated with inflammatory bowel disease.
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影响因子：
5.3
作者：
Burch, Jason M.;Mashayekh, Siavash;Grimes, Catherine L.
通讯作者：
Grimes, Catherine L.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
15
作者：
Grimes CL;Ariyananda Lde Z;Melnyk JE;O'Shea EK
通讯作者：
O'Shea EK
影响因子：
8
作者：
Guan, RJ;Brown, PH;Mariuzza, RA
通讯作者：
Mariuzza, RA
DOI：
10.1016/0006-291x(74)90458-6
发表时间：
1974-01-01
影响因子：
3.1
作者：
ELLOUZ, F;ADAM, A;LEDERER, E
通讯作者：
LEDERER, E