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Bernhard Hube (2011-2017)

Survival and proliferation of human pathogenic Candida species within phagocytes

Candida albicans and C. glabrata are important fungal pathogens, which can cause life-threatening systemic infections in immunocompromised patients. Both fungi not only survive phagocytosis by macrophages, but even proliferate intracellularly and escape. The two species have both common and distinct strategies: for example, both fungi block phagosomal acidification, presumably by active alkalinisation and manipulation of phagosome maturation. C. albicans escapes from macrophages via filamentation and hypha-associated activities, while C. glabrata replicates as yeast cells until a critical mass is reached and host cells burst.

In the first phase of the priority programme, we identified a series of C. glabrata genes associated with intracellular survival in macrophages. C. glabrata was found to reside in phagosomes with late endosomal, but not lysosomal properties. Macrophage activation in terms of cytokine and ROS production, as well as induction of MAPK signalling pathways upon C. glabrata phagocytosis was low, suggesting that intracellular replication is an immune evasion strategy of the fungus. We have demonstrated that C. glabrata can actively alkalinise its surroundings and this may be responsible for counteracting phagosome acidification. We also found that protein mannosylation likely plays a key role in alterations of phagosomal properties by C. glabrata. In further preliminary work, we discovered a hypha-associated polypeptide of C. albicans, Ece1, which is potentially processed into distinct peptides. One of these peptides has the capacity to efficiently produce pores in host membranes and lyses host cells.

In the second round of the priority programme, we aim to (I) investigate the functions of the C. glabrata genes shown to be important for macrophage intracellular survival and replication. This includes genes involved in alkalinisation and mannosylation, as well as calcium signalling and biotin acquisition. We further plan to elucidate fungal strategies to gain iron within the phagosome and to escape from macrophages. Also, we aim to determine whether the intracellular lifestyle of C. glabrata protects the fungus from other immune cells.

In a second block of experiments, we aim to (II) elucidate the function of the C. albicans protein Ece1 in fungus-macrophage interaction. We propose that intra-macrophage pore formation by Ece1 allows the influx and efflux of molecules, causes sequential phagosome/plasma membrane lysis and may facilitate the translocation of effector proteins into the host cytoplasm. We plan to elucidate the role of Ece1 in host cell manipulation, phagosome maturation, nutrient acquisition and survival in macrophages. Furthermore, we will analyse the impact of Ece1 on host cell lysis and escape from the phagosome and from macrophages.

 

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