Phagocytosis-independent antimicrobial activity of mast cells by formation of extracellular traps: cellular receptors involved, underlying molecular mechanism and pathogen countermeasures

肥大细胞的一个重要效应功能是促进机体对病原体的天然免疫。我们先前已经报道，MC可以释放由DNA和颗粒蛋白组成的细胞外陷阱(MCET)，诱捕并杀死病原体。这一建议的一个主要目标是确定外在的特定信号以及下游信号通路，这些信号通路将促使MCs释放MCET以响应病原体。在第一个资助期间，我们使用转录微阵列数据结合生物信息学来识别特定的转录特征，这些特征区分MC对病原体的反应和聚集的IgE刺激后MC的脱颗粒。这些研究将在第二个资助期进行，对转录数据进行实验验证，并确定导致观察到的基因表达变化的上游原因(S)以及可能导致这些变化的具体分子机制(S)。从治疗的角度来看，对这些途径的充分了解将导致制定策略来操纵MC对脱颗粒和生存或MCET的释放和死亡的反应。这项提议的另一个目标是更好地了解某些病原体为逃避MCET的抗菌活性而制定的策略。在感染过程中干扰这些策略可以提供一种治疗工具，以实现有效的病原体清除。

An important effector function of mast cells (MCs) is to promote innate immunity against microbial pathogens. We have previously reported that MCs can release extracellular traps (MCETs) composed of DNA and granule proteins that ensnare and killed pathogens. A major goal of this proposal is to identify the extrinsic specific signals as well as downstream signaling pathways that will commit MCs to release MCETs in response to pathogens. During the first funding period we have used transcriptional microarray data combined with bioinformatics to identify specific transcriptional signatures that discriminates the MC response to pathogens from MC degranulation after stimulation with aggregated IgE. These studies will be pursued during the second funding period by experimental validation of the transcription data as well as by the identification of the upstream cause(s) leading to the observed gene expression changes and the specific the molecular mechanism(s) that could have caused those changes. From a therapeutic perspective, a full understanding of these pathways will lead to the development of strategies to manipulate the MC response towards degranulation and survival or towards the release of MCETs and death. An additional goal of this proposal is to achieve a better understanding of the strategies developed by certain pathogens to escape the antimicrobial activity of MCETs. Interfering with these strategies during the infection process can provide a therapeutic tool to achieve efficient pathogen clearance.