Verbeurgt Christophe, Veithen Alex, Carlot Sébastien, Tarabichi Maxime, Dumont Jacques E, Hassid Sergio, Chatelain Pierre
Department of Otorhinolaryngology, Erasme University Hospital, Free University of Brussels, Brussels, Belgium.
ChemCom S.A., Brussels, Belgium.
PLoS One. 2017 Sep 13;12(9):e0181302. doi: 10.1371/journal.pone.0181302. eCollection 2017.
T2R38 has been shown to be a specific bacterial detector implicated in innate immune defense mechanism of human upper airway. Several clinical studies have demonstrated that this receptor is associated with the development of chronic rhinosinusitis (CRS). T2R38 was previously reported to bind to homoserine lactones (HSL), quorum sensing molecules specific of Pseudomonas Aeruginosa and other gram negative species. Nevertheless, these bacteria are not the major pathogens found in CRS. Here we report on the identification of bacterial metabolites acting as new agonists of T2R38 based on a single cell calcium imaging study. Two quorum sensing molecules (Agr D1 thiolactone from Staphylococcus Aureus and CSP-1 from Streptococcus Pneumoniae) and a list of 32 bacterial metabolites from pathogens frequently implicated in CRS were tested. First, we observed that HSL failed to activate T2R38 in our experimental system, but that the dimethylsulfoxide (DMSO), used as a solvent for these lactones may, by itself, account for the agonistic effect previously described. Secondly, we showed that both Agr D1 thiolactone and CSP-1 are inactive but that at least 7 bacterial metabolites (acetone, 2-butanone, 2-pentanone, 2-methylpropanal, dimethyl disulfide, methylmercaptan, γ-butyrolactone) are able to specifically trigger this receptor. T2R38 is thus much more broadly tuned for bacterial compounds than previously thought.
T2R38已被证明是一种参与人类上呼吸道先天免疫防御机制的特异性细菌探测器。多项临床研究表明，该受体与慢性鼻窦炎（CRS）的发病有关。此前有报道称，T2R38可与高丝氨酸内酯（HSL）结合，HSL是铜绿假单胞菌和其他革兰氏阴性菌特有的群体感应分子。然而，这些细菌并非CRS中发现的主要病原体。在此，我们基于单细胞钙成像研究报告了作为T2R38新激动剂的细菌代谢产物的鉴定。测试了两种群体感应分子（金黄色葡萄球菌的Agr D1硫内酯和肺炎链球菌的CSP-1）以及32种来自CRS常见病原体的细菌代谢产物。首先，我们观察到在我们的实验系统中HSL未能激活T2R38，但用作这些内酯溶剂的二甲基亚砜（DMSO）本身可能是先前描述的激动效应的原因。其次，我们表明Agr D1硫内酯和CSP-1均无活性，但至少7种细菌代谢产物（丙酮、2-丁酮、2-戊酮、2-甲基丙醛、二甲基二硫、甲硫醇、γ-丁内酯）能够特异性激活该受体。因此，T2R38对细菌化合物的调节范围比以前认为的要广泛得多。
