Identification and characterization of mast cell functions in Sporothrix schenckii infections

申克孢子丝菌感染中肥大细胞功能的鉴定和表征

• 批准号: 242029477
• 负责人: Professor Dr. Marcus Maurer
• 金额: --
• 依托单位: Dermatology and Venerology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242029477?language=en
• 关键词: Identification; characterization; mast; cell; functions

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.

近年来，在欧洲和中国，侵入性真菌感染的发病率都大大增加。原因之一是免疫功能低下的患者人群不断增长。当前的治疗选择还不够，侵入性真菌感染的死亡率仍然不可接受。为了改变这一点，我们需要更好地表征严重真菌感染的发病机理。在此基础上，我们可以开发新颖和更好的治疗选择。植物细胞（MCS）在抗真菌反应中表达了几个至关重要的受体和介体。对真菌病原体的宿主防御反应具有许多针对细菌和寄生虫的MC驱动免疫反应的特征。因此，我们假设MCS在针对真菌的宿主防御反应中起着重要作用，而MC靶向的干预措施可以帮助改善对真菌感染的保护和解决。为了检验这一假设，我们将使用Sporothrix Schenkii（Spor）作为真菌的原型病原体建立真菌感染小鼠模型。 SPOR通常引起免疫能力个体的皮肤感染，但在免疫功能低下的患者中严重侵入性感染。具体而言，我们将通过MC缺陷小鼠及其正常的野生型同窝仔的临床和组织病理学分析来评估和比较孢子感染。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，我们将确定肥大细胞及其产物对SPOR存活和致病性的影响。最后，我们要研究肥大细胞通过分析迁移和激活树突状细胞（DC）的相关性，这已证明在孢子感染中至关重要。该项目将有助于更好地描述MC在对真菌感染的宿主防御反应中的作用。更重要的是，我们的项目可以帮助提供更好的工具和新型的治疗选择，以治疗感染SPOR和其他真菌病原体的患者。