Survival and proliferation of human pathogenic Candida species within phagocytes

光滑念珠菌是一种重要的真菌病原体，可导致免疫功能低下患者发生危及生命的全身感染。然而，其他研究和我们的研究发现，C. glabrata在小鼠中几乎没有炎症，但可以在令人惊讶的长时间内从感染的动物中重新分离。此外，我们发现分离的免疫细胞如巨噬细胞对C.光滑的相反，真菌不仅能够生存，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，这通常会导致吞噬的微生物的杀伤，被这种病原体积极破坏。特别是，吞噬体酸化被活的但不是被杀死的真菌阻断。本项目拟对C. glabrata是避免巨噬细胞杀伤和阐明真菌抑制炎症反应的策略所必需的。为此，我们将筛选C的库。glabrata突变体的能力，操纵吞噬成熟和吞噬细胞内生存。此外，我们将分析基因表达的吞噬反应和puronectin参与的过程中。通过分子生物学和细胞生物学的方法，我们的目标是阐明C。glabrata能够持续存在于免疫细胞中，并确定这一过程对发病的意义。

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.