Phosphate Signalling in Cryptococcus- a passport to the CNS

Associate Professor Julie Djordjevic
Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research (WIMR) and Sydney Medical School, Westmead, The University of Sydney
4 August 2017 - 3:00pm
Rountree Room 356, Level 3, Biological Sciences Building D26

Invasive fungal infections caused by Candida, Aspergillus and Cryptococcus species are responsible for high rates of morbidity and mortality world-wide. The AIDS-related fungal pathogen, Cryptococcus neoformans, initially establishes a lung infection. However, patients often present with meningoencephalitis, which is fatal without treatment. Understanding how C. neoformans disseminates is therefore critical to inform new therapeutic strategies. 

C. neoformans tolerates different microenvironments during host infection, which impact its ability to derive nutrients. In contrast to the blood, which is mildly alkaline, C. neoformans grows in a more acidic environment in lung and brain due to the formation of cryptococcomas. C. neoformans must therefore obtain an adequate supply of nutrients from within each of these host niches to tolerate host stress and establish infection.  

Phosphorus in the form of phosphate is essential for numerous cellular processes, including membrane, nucleic acid and ATP synthesis. It is also required for synthesis of inositol polyphosphates, which are crucial for fungal virulence in mouse models. Phosphate acquisition by fungi is regulated by the PHO signalling cascade, which is activated when intracellular phosphate levels fall.

The work presented demonstrates that blocking PHO pathway activation prevents dissemination of fungal infection from lung to brain in murine models. The work also shows that fungal growth at alkaline pH mimics phosphate starvation, triggering upregulation of the PHO pathway to replenish phosphate stores, support fungal growth and promote stress tolerance, particularly in the blood.

Biography: Associate Professor Julie Djordjevic is Principal Research Fellow and head of the Fungal Pathogenesis Group within the Centre for Infectious Diseases and Microbiology (CIDM) at the Westmead Institute for Medical Research (WIMR)

She completed a PhD at the University of Queensland in 1995 and then a post-doctoral fellowship investigating the molecular basis of atherosclerosis. She then completed post-doctoral fellowships at Westmead Hospital investigating the mode of action of novel immunosuppressive and antimicrobial peptides, and mechanisms of HIV pathogenesis including the role of lipid rafts in the infection process.

In 2003, she joined WIMR to embark on a career understanding the pathogenesis of invasive fungal disease. During this time, she undertook a joint post-doctoral fellowship at the Medical University of South Carolina to determine the mode of secretion of the fungal “invasin”, phospholipase B, in the AIDS-related pathogen, Cryptococcus neoformans.

In 2005, she was appointed a tenured position with CIDM to establish her own research group.  Using Cryptococcus neoformans as a model, her broad research interests are elucidating mechanisms used by fungi to cause systemic infection in humans, with a view to exposing novel targets for antifungal drug development. Specifically, her group is interested in understanding how fungal virulence factors and cell wall components are secreted, and the role of phosphate homeostasis in disseminated infection and meningitis.