Interkingdom communication: understanding how mast cells translate and respond to bacterial quorum sensing signals

许多种类的细菌通过细胞密度依赖的信号系统相互交流，称为群体感应。这些信号由小的类细菌分子介导，并允许细菌群体协调它们的基因表达和活动。越来越明显的是，群体感应系统的某些成分也可以影响真核细胞的行为。特别令人感兴趣的是，新兴的数据表明，由革兰氏阴性菌，酰基高丝氨酸内酯（阿勒）产生的群体感应分子的某一类，可以调节哺乳动物的免疫反应。我实验室的初步数据表明，某些阿勒抑制肥大细胞对细菌成分和抗原的反应，而不影响细胞活力。肥大细胞在宿主防御中起着重要作用，充当免疫系统的哨兵，战略性地位于与我们的外部环境接触的部位。它们响应细菌感染而迅速激活，并且对于效应细胞如中性粒细胞的早期募集至关重要。因此，肥大细胞是一种高度相关的靶细胞，在其中研究这种知之甚少的王国间通讯形式，这种通讯形式可能在介导哺乳动物及其微生物群之间的有害和有益相互作用方面发挥重要作用。本申请中提出的实验将通过以下方式检查阿勒介导的肥大细胞功能调节：1）确定阿勒对肥大细胞活性的影响，2）描绘由阿勒调节的肥大细胞信号传导途径，3）鉴定阿勒的潜在哺乳动物受体。

Many species of bacteria communicate with each other through a cell density dependent signaling system, termed quorum sensing. These signals are mediated by small hormone-like molecules and allow a population of bacteria to co-ordinate their gene expression and activities. It is becoming evident that certain components of the quorum sensing system can also influence the behavior of eukaryotic cells. Of particular interest is the emerging data suggesting that a certain class of quorum sensing molecules produced by gram-negative bacteria, acyl homoserine lactones (AHL), can modulate mammalian immune responses. Preliminary data from my laboratory indicate that certain AHL inhibit mast cell responses to bacterial components and antigen without influencing cell viability. Mast cells play an important role in host defense, acting as sentinels of the immune system, strategically located at sites that interface with our external environment. They are rapidly activated in response to bacterial infection, and can be crucial for the early recruitment of effector cells such as neutrophils. Thus the mast cell is a highly relevant target cell in which to study this poorly understood form of inter-kingdom communication that likely plays an important role in mediating both detrimental and beneficial interactions between mammals and their microbiota. The experiments proposed in this application will examine AHL mediated regulation of mast cell function by; 1) determining the influence of AHL on mast cell activity, 2) delineating mast cell signaling pathways modulated by AHL, 3) identifying potential mammalian receptors for AHL.