Inter-kingdom Signalling: Modulation of Mast cells by Commensal Bacteria

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Background and Rationale: Mast cells long regarded as key effectors of human allergic disease are now considered primary inducers and amplifiers of both innate and adaptive immune responses. Their presence in high numbers in the airway and gut mucosa is indicative of their role as important gatekeepers/sentinels for fighting infectious organisms at these portals of entry. However, the position of mast cells on the frontline of defense against pathogens also suggests they may play an important role in fostering the host-microbiome relationship and maintaining the complex ecosystem of the super-organism. Based on our previous studies, and those of others, it appears that non-pathogenic bacteria can utilize distinct mechanisms to stabilize mast cells acting by direct cell-cell interaction, through secretion of mediators and possibly through the release of membrane micro-vesicles. We have also identified receptors and ion channels on the mast cell that are potential targets for novel bacterial signalling systems. Objectives: The long-term objective of this research program is to understand the molecular mechanisms underlying novel inter-kingdom communication systems and to contribute to our understanding of the role these systems play in shaping the relationship between bacteria and their mammalian hosts. The experiments proposed in this application will examine microbe-mediated regulation of mast cell function by pursuing the following specific aims: • Determine the influence of diverse non-pathogenic microbes, microbe shed microvesicles and metabolites on mast cell phenotype and function. • Determine the signaling pathways underlying the functional effects of microbes on mast cells. • Identify potential mast cell receptors involved in novel aspects of host/microbe interactions. Experimental approach: We will focus on the effect of strains of Lactobacilli and non-pathogenic E.coli on primary murine mast cells. We will examine the effect of direct exposure to whole bacteria, micro-vesicles and secreted products. In addition to assessing changes in mediator release and migration we will also investigate potential switching of mast cells to a regulatory phenotype. A combination of pharmacological approaches, mast cells from transgenics and electrophysiology will be employed to identify receptors, ion channels and pathways involved in transducing mast cell responses to bacteria signals. Outcomes: Completion of the proposed studies will provide us with a deeper understanding of the interactions between mammals and bacteria that extends beyond the traditional view of innate immunity. In addition to the identification of novel modes of inter-kingdom communication this study will provide insight into how symbiotic relationships shape mammalian physiology. As such this is foundational research with potentially wide-reaching implications for biological sciences.