Mechanisms of Fungal Adaptation to Micro-Niches within the Mammalian Brain

Cryptococcus neoformans is the predominant cause of lethal fungal meningitis in humans. In the brain, the fungus resides in large masses called cryptococcomas but may also reside within host immune cells. Fungal cells have different phenotypes depending on which of these niches they inhabit in the brain. Yet, how this niche-specific adaptation arises and its consequences for pathology are not known. We previously found that fungi residing inside host cells are protected against copper starvation, whereas extracellular yeast upregulated copper importers to protect against a low copper environment. Our initial experiments show that these differential responses may influence fungal stress adaptation and development of drug resistance. In this project, we aim to define the mechanisms regulating niche-specific fungal adaptation and how this impacts development of drug resistance in the host. For that, we will use a combination of RNA sequencing and fungal mutants to identify the genes regulating adaptation to brain micro-environments, utilising an in vivo mouse model of cryptococcal meningitis and a cutting-edge ex vivo organotypic brain slice infection model using mouse and human tissue. Collectively, this work will provide a step-change in our understanding of the in-host behaviour of a prolific fungal pathogen.