A therapeutic approach to enhance innate defense mechanisms against toxins and venoms - mast cell proteases to the rescue

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Mast cells (MC) are important effector cells not only in allergic reactions but also in innate immune responses against bacteria. We and others have previously shown that the release of proinflammatory mediators from MC can combat bacterial infections by direct killing of the microbes and by recruitment of other inflammatory cells. Within the first funding period, we have identified MC as crucially important for the control of bacterial toxin mediated skin inflammation. Furthermore, we were able to show that MC can also control various endogenous and exogenous toxins such as neurotensin, vasoactive intestinal peptide and the venom from various snakes, scorpions, and Heloderma. As MC were able to dramatically reduce the toxicity associated with most of these toxins, we now aim to translate these findings into the human system, characterize the mechanisms of detoxification and to ultimately develop the basis for a pharmacologic approach for the treatment of local effects of toxins. Therefore, we will further develop and validate a model for toxicity testing without the need for vertebrates, identify and characterize the optimal MC derived protease and the cleavage specificity of these proteases and characterize in detail the inflammatory and anti-inflammatory potential of the respective proteases. With these investigations, we aim to provide proof of concept for a potential therapeutic approach using recombinant human proteases for the treatment of envenomations or other local intoxications.