Identification and characterization of the mechanisms of mast cell-mediated protection from bacterial skin wound infection by Pseudomonas aeruginosa

肥大细胞（MCs）一直被认为是一种可有可无的细胞类型，它似乎只负责恼人的，有时甚至是危及生命的过敏反应症状。然而，在过去的几年里，很明显，MCs对于宿主对微生物的最佳防御也至关重要，它们在先天免疫反应中充当哨兵和效应细胞。我们和其他人已经描述了MCs对降低小鼠细菌感染的发病率和死亡率至关重要。为了进一步研究MCs在防御临床相关细菌性皮肤感染中的先天免疫功能，我们建立了小鼠皮肤创面感染模型。通过使用该模型，我们能够证明MCs通过控制细菌负担对感染伤口的正常愈合至关重要。在这里，我们建议确定导致最佳MC功能防御细菌性皮肤感染的机制和相关信号。为此，我们将采用广泛的体外和体内分析来识别和表征信号，这可能最终导致宿主对细菌的反应得到改善，并将提供证据证明这一原理也适用于人类皮肤。因此，我们提出了一种治疗皮肤细菌感染的新策略，该策略将在体外细菌皮肤感染模型中评估其疗效。我们假设，这种新的治疗策略将提供一种预防性方法，以降低感染高风险个体的细菌感染风险，并提供一种替代治疗选择，以对抗对常见抗菌药物具有耐药性的细菌。

Mast cells (MCs) have long been thought to be a dispensable cell type, which seemed only responsible for the annoying and sometimes even life threatening symptoms of allergic reactions. Over the last years, however, it became evident that MCs are also crucially important for optimal host defense against microbes, where they act as sentinels and effector cells of the innate immune responses. We and others have described that MCs are crucial to reduce morbidity and mortality of bacterial infections in mice. To further investigate the innate immune function of MCs in the defense of clinically relevant bacterial skin infections, we established a murine model of skin wound infection. By using this model we were able to demonstrate that MCs are essential for normal healing of infected wounds by controlling the bacterial burden. Here, we propose to identify the mechanisms and relevant signals that lead to an optimal MC function to defend bacterial skin infection. To this end, we will employ extensive in vitro and in vivo analyses to identify and characterize signals, which may ultimately lead to an improved host response against bacteria and will provide evidence that this principle is also effective in human skin. We therefore suggest a novel strategy for the treatment of bacterial infections in the skin, which will be assessed for efficacy in ex vivo models of bacterial skin infections. We hypothesize that such novel treatment strategies will provide a prophylactic approach to reduce the risk of bacterial infections in individuals with high risks of infections and an alternative therapeutic option to battle against bacteria resistant to common antimicrobial agents.