Identification and characterization of mast cell functions in Sporothrix schenckii infections

近年来，侵袭性真菌感染的发病率在欧洲和中国都急剧增加。其中一个原因是免疫功能低下的患者人数不断增加。目前的治疗选择是不够的，侵袭性真菌感染的死亡率仍然高得令人无法接受。为了改变这一点，我们需要更好地描述严重真菌感染的发病机制。在此基础上，我们可以开发新的和更好的治疗方案。肥大细胞（MC）表达抗真菌反应中的几个关键受体和介质。宿主对真菌病原体的防御反应具有许多MC驱动的针对细菌和寄生虫的免疫反应的特征。因此，我们假设MC在宿主对真菌的防御反应中起着重要作用，MC靶向干预有助于提高真菌感染的保护和解决。为了验证这一假设，我们将使用申克孢子丝菌（Spor）作为真菌的原型病原体建立真菌感染小鼠模型。Spor通常在免疫功能正常的个体中引起皮肤感染，但在免疫功能低下的患者中引起严重的侵入性感染。具体来说，我们将评估和比较孢子感染的临床和组织病理学分析MC缺陷型小鼠和正常野生型同窝出生。接下来，我们将通过分析脱粒、细胞因子释放、增殖和迁移来评估肥大细胞对Spor的反应，并确定肥大细胞及其产物对Spor存活和致病性的影响。最后，我们想通过分析树突状细胞（DC）的迁移和激活来研究肥大细胞诱导Th1 CD4细胞应答的相关性，树突状细胞（DC）在孢子感染中已被证明是至关重要的。该项目将有助于更好地表征MC在宿主对真菌感染的防御反应中的作用。更重要的是，我们的项目可以帮助提供更好的工具和新的治疗选择，用于治疗感染Spor和其他真菌病原体的患者。

In recent years, the incidence of invasive fungal infections has increased dramatically both in Europe and in China. One of the reasons for this is the growing population of immunocompromised patients. Current treatment options are not sufficient and the mortality of invasive fungal infections remains unacceptably high. To change this, we need to better characterize the pathogenesis of severe fungal infections. On this basis we can develop novel and better treatment options.Mast cells (MCs) express several crucial receptors and mediators in antifungal responses. The host defence responses to fungal pathogens share many features of MC-driven immune responses against bacteria and parasites. We, therefore, hypothesize that MCs play an important role in host defence responses against fungi and that MC-targeted interventions can help to improve the protection from and resolution of fungal infections. To test this hypothesis, we will establish a fungal infection mouse model using Sporothrix schenkii (Spor) as a prototype pathogen for fungi. Spor commonly causes infections of the skin in immunocompetent individuals but severe invasive infections in immunocompromised patients. Specifically, we will assess and compare Spor-infections both clinically and by histopathologic analyses in MC-deficient mice and their normal wild type littermates. Next, we will assess mast cell responses to Spor by analysing degranulation, cytokine release, proliferation and migration, and we will determine the effects of mast cells and their products on Spor survival and pathogenicity. Finally, we want to investigate the relevance of mast cells for inducing Th1 CD4 cell responses by analysing migration and activation of dendritic cells (DCs) which has been shown to be crucial in Spor-Infection. This project will help to better characterize the role of MCs in host defence reactions against fungal infections. More importantly, our project could help to provide better tools and novel therapeutic options for the treatment of patients infected with Spor and other fungal pathogens.