Microevolution of pathogenic yeasts during interactions with the host immune system

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Candida albicans and C. glabrata are the two most important causes of candidemia – a life-threatening, systemic fungal infection. As commensals and opportunistic pathogens, these yeasts have to be able to adapt to the many different niches inside their human host. We aim to use in vitro and in vivo forced microevolution experiments, both to determine the ability of these fungi to adapt to host-induced stresses, and to identify novel potential pathogenicity factors. To this end, we will first expose C. glabrata to macrophages in a serial passage setup and follow the genetic, phenotypic, and transcriptional changes induced by constant host-fungus interaction. In a second approach, we will use a mutant of C. albicans, which is unable to form hyphae, a property which is essential for virulence and escape from phagocytes. Again, the mutant will be exposed to macrophages in serial passages and its ability to survive and regain hyphal formation by transcriptional rewiring will be followed. Finally, we will investigate the ability of C. albicans to adapt to different host niches. In a murine infection model, we will follow the genetic and transcriptional (transcriptional rewiring) changes as well as changes of organotropism of the fungus after serial re-isolation and infection, and we will compare this to data from a collection of clinical isolates obtained from different host niches. We expect to find adaptations and mechanisms in both fungi, which may constitute novel, 'hidden' pathogenicity factors.