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

许多种类的细菌通过一种依赖于细胞密度的信号系统相互交流，这种系统被称为群体感应。这些信号是由小的激素样分子介导的，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，新出现的数据表明，革兰氏阴性细菌产生的一类群体感应分子，酰基高丝氨酸内酯（AHL），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，作为免疫系统的哨兵，战略性地位于与我们外部环境接口的位置。它们在对细菌感染的反应中被迅速激活，并且对于中性粒细胞等效应细胞的早期募集至关重要。因此，肥大细胞是一个高度相关的靶细胞，研究这种知之甚少的王国间通信形式，可能在调节哺乳动物与其微生物群之间有害和有益的相互作用中发挥重要作用。本应用程序中提出的实验将通过；1)确定AHL对肥大细胞活性的影响，2)描绘AHL调节的肥大细胞信号通路，3)鉴定AHL潜在的哺乳动物受体。

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.