Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153.
J Immunol. 2014 May 15;192(10):4813-20. doi: 10.4049/jimmunol.1303369. Epub 2014 Apr 16.
Host inflammatory responses against pathogenic organisms can be abrogated by commensals; however, the molecular mechanisms by which pathogenesis is prevented are still poorly understood. Previous studies demonstrated that administration of a single dose of Bacillus subtilis prevented disease and inflammation by the enteric mouse pathogen Citrobacter rodentium, which causes disease similar to the human pathogen enteropathogenic Escherichia coli. No protection was observed when an exopolysaccharide (EPS)-deficient mutant of B. subtilis was used, suggesting that EPS are the protective factor. In this study, we isolated and characterized EPS and showed that they also prevent C. rodentium-associated intestinal disease after a single injection. Protection is TLR4 dependent because EPS-treated TLR4 knockout mice developed disease. Furthermore, protection could be conveyed to wild-type mice by adoptive transfer of macrophage-rich peritoneal cells from EPS-treated mice. We found that EPS specifically bind peritoneal macrophages, and because mice lacking MyD88 signaling in myeloid cells were not protected by EPS, we conclude that bacterial EPS prevent colitis in a TLR4-dependent manner that requires myeloid cells. These studies provide a simple means of preventing intestinal inflammation caused by enteric pathogens.
定植菌能消除机体针对病原微生物的炎症反应，但目前我们仍不清楚预防发病的具体分子机制。先前的研究表明，枯草芽孢杆菌单次给药能预防肠道病原体鼠柠檬酸杆菌引发的疾病和炎症，而鼠柠檬酸杆菌能引起类似于人类病原体肠致病性大肠杆菌的疾病。当使用枯草芽孢杆菌缺乏胞外多糖（EPS）的突变体时，没有观察到保护作用，这表明 EPS 是保护因子。在本研究中，我们分离并鉴定了 EPS，并表明单次注射 EPS 也能预防柠檬酸杆菌相关的肠道疾病。这种保护作用依赖于 TLR4，因为 EPS 处理的 TLR4 基因敲除小鼠会发展为疾病。此外，通过从 EPS 处理的小鼠体内过继转移富含巨噬细胞的腹膜细胞，可以将保护作用传递给野生型小鼠。我们发现 EPS 能特异性结合腹膜巨噬细胞，而骨髓细胞中缺乏 MyD88 信号转导的小鼠则不能被 EPS 保护，因此我们得出结论，细菌 EPS 通过依赖 TLR4 的方式来预防结肠炎，而这种方式需要髓系细胞。这些研究为预防肠道病原体引起的肠道炎症提供了一种简单的方法。
