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。造成这种情况的原因之一是免疫功能低下的患者人数不断增加。目前的治疗方案是不够的，侵袭性真菌感染的死亡率仍然高得令人无法接受。为了改变这种情况，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（MCs）在抗真菌反应中表达几种重要的受体和介质。宿主对真菌病原体的防御反应与mc驱动的针对细菌和寄生虫的免疫反应具有许多特征。因此，我们假设MCs在宿主对真菌的防御反应中发挥重要作用，并且针对mc的干预可以帮助提高对真菌感染的保护和解决。为了验证这一假设，我们将以申氏孢子菌（Sporothrix schenkii, Spor）作为真菌的原型病原体，建立真菌感染小鼠模型。孢子虫通常在免疫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袭性感染。具体来说，我们将评估和比较mc缺陷小鼠及其正常野生型幼崽的临床和组织病理学分析。接下来，我们将通过分析脱颗粒、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，我们希望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细胞反应的相关性，树突状细胞（dc）已被证明在孢子感染中至关重要。该项目将有助于更好地表征MCs在宿主对真菌感染的防御反应中的作用。更重要的是，我们的项目可以为Spor和其他真菌病原体感染患者的治疗提供更好的工具和新的治疗选择。

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.