Survival and proliferation of human pathogenic Candida species within phagocytes

吞噬细胞内人类致病性念珠菌的存活和增殖

• 批准号: 181921746
• 负责人: Professor Dr. Bernhard Hube
• 金额: --
• 依托单位: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. Hans-Knöll-Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/181921746?language=en
• 关键词: Survival; proliferation; human; pathogenic; Candida

Candida glabrata is an important fungal pathogen, which can cause life-threatening systemic infections in immunocompromised patients. Yet, other and our studies found that C. glabrata elicits little inflammation in mice, but can be re-isolated over a surprisingly long period from infected animals. Furthermore, we found that isolated immune cells such as macrophages show little proinflammatory responses to C. glabrata. Instead, the fungus is not only able to survive, but even replicates inside these phagocytes. Our data suggests that the normal events of phagosome maturation, which normally lead to the killing of phagocytosed microbes, are actively disrupted by this pathogen. In particular, phagosomal acidification is blocked by viable, but not killed fungi. In this project we plan to identify and investigate genes and activities of C. glabrata necessary to avoid killing by macrophages and to elucidate fungal strategies to suppress an inflammatory response. To this end, we will screen libraries of C. glabrata mutants for their ability to manipulate phagosome maturation and to survive inside the phagocyte. Furthermore, we will analyse gene expression in response to phagocytosis and characterise the genes putatively involved in the process. By using molecular and cell biology approaches we aim to elucidate the mechanism by which C. glabrata is able to persist in immune cells, and to determine the significance of this process for pathogenesis.

光念珠菌是一种重要的真菌病原体，可引起危及生命的全身感染免疫功能低下的患者。然而，其他和我们的研究发现，C. glabrata在小鼠中引起的炎症很小，但可以从感染的动物中重新分离出很长一段时间。此外，我们发现分离的免疫细胞如巨噬细胞对光棘球蚴几乎没有促炎反应。相反，真菌不仅能够存活，甚至还能在这些吞噬细胞内复制。我们的数据表明，吞噬体成熟的正常事件通常导致被吞噬的微生物被杀死，被这种病原体积极地破坏。特别是，吞噬体酸化被活菌阻断，而不是被杀死的真菌。在这个项目中，我们计划鉴定和研究C. glabrata避免巨噬细胞杀死所需的基因和活性，并阐明真菌抑制炎症反应的策略。为此，我们将筛选光斑梭菌突变体文库，以了解它们操纵吞噬体成熟和在吞噬细胞内存活的能力。此外，我们将分析基因表达对吞噬反应和特征的基因推定参与这一过程。通过分子生物学和细胞生物学的方法，我们旨在阐明光棘球蚴能够在免疫细胞中持续存在的机制，并确定这一过程在发病机制中的意义。