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Mitochondria as regulators of fungal virulence

Final Report Summary - MITOFUN (Mitochondria as regulators of fungal virulence)

The primary objective of MitoFun was to determine the molecular basis of hypervirulence in an important and unusual human fungal pathogen, Cryptococcus gattii, and to use these findings as a paradigm to test to what extent these mechanisms are conserved across other similar pathogens. Prior to MitoFun commencing, we had demonstrated the genetic dependence of hypervirulence in the so-called Pacific Northwest Outbreak strains of C. gattii and associated this trait with an unusual mitochondrial morphology in these fungi. Our proposal thus focused on exploiting these findings to determine the underlying pathway and mechanism that facilitates the rapid intracellular growth of these strains within the human host.

Over the course of the project, we made a number of important and hitherto unknown discoveries. Specifically, we discovered:
a) that extracellular vesicles, shed by the fungus, help regulate virulence within the host
b) that host cells have a conserved inflammatory pathway that helps to 'eject' fungi
c) that hybridisation and novel gene exchange alters transcriptional pathways and has a lasting impact on virulence traits

In addition, we worked with collaborators in several different fields to develop technologies and tools that have a wide impact, beyond the direct questions of MitoFun. These include novel mass-spectrometry approaches for fungal diagnosis, novel decontamination strategies for fungi, and some promising 'redeployment' options for antifungal drug therapy.