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

许多种类的细菌通过依赖于细胞密度的信号系统相互通信，称为群体感应。这些信号是由类似激素的小分子介导的，并允许一群细菌协调他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组件也可以影响真核细胞的行为。尤其令人感兴趣的是，新出现的数据表明，由革兰氏阴性细菌产生的某种群体感应分子，即酰基高丝氨酸内酯(AHL)，可以调节哺乳动物的免疫反应。来自我的实验室的初步数据表明，某些AHL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扮演着重要的角色，它是免疫系统的哨兵，战略性地位于与外部环境相连接的位置。它们在细菌感染时被迅速激活，对于中性粒细胞等效应细胞的早期招募至关重要。因此，肥大细胞是研究这种鲜为人知的跨界交流形式的高度相关的靶细胞，这种形式可能在哺乳动物与其微生物群之间的有害和有益的相互作用中发挥重要作用。本申请中提出的实验将通过以下几个方面来研究AHL对肥大细胞功能的调节：1)确定AHL对肥大细胞活性的影响；2)描绘由AHL调控的肥大细胞信号通路；3)确定AHL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.