Survival and proliferation of human pathogenic Candida species within phagocytes

The opportunistic Candida species, C. albicans and C. glabrata, can colonize multiple organs during systemic infection and face different defense activities of the host. Immune cells, like macrophages, ingest fungal cells into phagosomes facing a hostile environment with low nutrient levels. C. albicans and C. glabrata cells adapt to this limitation inside the phagosome by adjusting their central metabolic pathways. The prerequisite for vitamins cannot be bypassed as these are cofactors, like biotin for which both Candida species are auxotrophic. This thesis aimed to gain new insights into the relevance of fungal biotin acquisition on fungal proliferation in specific host niches, such as the phagosome of macrophages, and virulence. The identified biotin transporter gene VHT1 in C. albicans and C. glabrata contributed to biotin-dependent growth and VHT1 transcription was shown to be regulated by biotin availability and the transcription factor Vhr1. The impact of Vht1-mediated biotin acquisition for intraphagosomal proliferation together with the increased VHR1 and VHT1 expression in phagocytosed fungal cells suggested a limited biotin access in Candida-containing phagosomes. The efficient colonization of C. glabrata and C. albicans in distinct organs and for virulence of C. albicans during systemic candidiasis were dependent on Vht1-mediated biotin acquisition. Overall, these results propose that both species experience biotin limitation in certain host niches and that Vht1-dependent biotin import is a mechanism to overcome this limitation. The evolutionary adaptation of pathogenic Candida species may have originated from ancient interactions with environmental amoebae. Peroxiredoxin-mediated redox homeostasis was essential for survival of C. parapsilosis in amoebae and macrophages. These data showed the importance of micronutrient and redox homeostasis as counterstrategies of pathogenic Candida species to survive phagocytosis and pivotal virulence determinants.