Survival and proliferation of human pathogenic Candida species within phagocytes

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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.