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

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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.