BSc (University of Melbourne) Genetics, PhD (University of Melbourne) Genetics, GCEd (University of Queensland) Higher Education
Position: 
Associate Professor
Room: 
358
Phone: 
+61 7 336 54868
Biography: 

I completed my PhD in the Department of Genetics at the University of Melbourne, then moved to Durham, North Carolina as a postdoctoral fellow at the Duke University Medical Center in 2002. I returned to Australia as Senior Lecturer in the School of Chemistry and Molecular Biosciences at the University of Queensland in 2006.

Brief Research Description: 
Sex virulence and evolution in pathogenic fungi
Research Focus and Collaborations: 

 

With the growth of immunocompromised patient populations due to the AIDS pandemic and increases in immune system-suppressing medical interventions, infection by fungal pathogens has become a significant cause of morbidity and mortality. Of these, meningitis caused the yeast Cryptococcus neoformans is one of the most common life-threatening opportunistic infections in individuals with AIDS. Upon inhalation, Cryptococcusdisseminates to the central nervous system to cause meningoencephalitis that is invariably fatal if untreated. It has been estimated that up to 30% of AIDS patients in parts of Africa develop cryptococcal meningoencephalitis and the most recent data from the CDC estimates there are up to 1,000,000 deaths attributable to these infections each year. Collaborating with a number of groups in Australia and abroad, my laboratory employs molecular genetic and genomic approaches in the study of C. neoformans to understand how this pathogen evolves during infection of humans, and how we can exploit these changes in the development of urgently needed antifungal therapies.

Purine metabolism as an antifungal target
The mortality rate for C. neoformans infection approaches 20% in Australia even with ideal treatments, and in some parts of Africa can be up to 100%. Despite this high mortality rate, treatment for this infection has not changed significantly in over a decade. Novel antifungal agents with broad spectrum that are nontoxic, affordable and synergistic are therefore urgently required in our fight against this infection. Instead of targeting fungal-specific components, we are exploiting the purine biosynthesis pathway. We have extensively characterised several genes in this pathway, identifying those that are required for pathogenicity in multiple animal models. Through collaboration with the structural biology group of Bostjan Kobe (SCMB) and the drug development team of Matt Cooper (IMB), we seek to develop a new era of antifungals that act by modulating purine metabolism, enabling more efficient treatment of cryptococcal meningoencephalitis and other systemic mycoses.

The role of nitrogen metabolism during infection
Proper regulation of metabolism is essential to maximise fitness of organisms in their chosen environmental niche, particularly for an organism like C. neoformans that originates in nutrient-rich pigeon guano but may end up exposed to the hostile host environment during infection. We are invesitgating the regulatory paradigm of nitrogen metabolite repression, a phenomenon in fungi that enables preferential utilisation of more easily assimilated nitrogen sources such as ammonium in order to conserve resources. Using our understanding of nitrogen regulation we are now dissecting a variety of nitrogen metabolic pathways and investigating their importance during infection, and how they can be used to manipulate the host environment to create a more hospitable niche for C. neoformans survival.

Evolution of Cryptococcus during infection of humans
Following the initial infection, relapse of cryptococcal meningoencephalitis due to reemergence of the original infecting strain is common, particularly in patients not undergoing maintenance therapy or ART. While this can be due to patient nonadherence to prophylactic maintenance therapy, the reemergence can be caused by the infecting strain developing drug resistance, changes in virulence-associated traits or unknown mechanisms.Analysis of serial isolates (representing an initial infection isolate, and isolates subsequently collected upon relapse) has indicated that the majority of clinical recurrences result from persistence of a single strain rather than due to coinfection or reinfection with a new strain. However, these chromosomes of these strains have often undergone gross rearrangements during infection, a process that is often coincident with changes in known virulence factors. Using whole genome sequencing, comparative genomics and molecular genetic techniques we are identifying these changes to provide new insights into mechanisms of fungal pathogenesis.

Funded Projects: 

NHMRC Project Grant 2015-2017
Acetohydroxyacid synthase: A new drug target for human fungal pathogens
Total value of grant: $520,106 (Co-Chief Investigators A/Prof Luke Guddat, A/Prof Craig Williams)

NHMRC Project Grant 2013-2015
Purine metabolism as an antifungal drug target
Total value of grant: $679,893 (Co-Chief Investigator Mark Butler)
 

NHMRC Project Grant 2011-2013
Targeting acetohydroxyacid synthase to discover new antifungal agents
Total value of grant: $464,615 (Co-Chief Investigators A/Prof Luke Guddat, Jian-Guo Wang)

UQ Major Equipment and Infrastructure 2011
Cell culture facilities for studying host-pathogen interactions and immune function
Total value of grant: $198,168 (Co-Chief Investigators Kate Stacey, Mark Schembri, Mark Walker, Alastair McEwan, Alex Khromykh, Paul Young, Roy Hall, Justine Hill, Istvan Toth, Scott Beatson, Melissa Brown, Joe Rothnagel, Stuart Kellie)

ARC Discovery Projects 2010-2012
Understanding an exotic disease: Initiation of sex and infection by the sugarcane smut Ustilago scitaminea
Total value of grant: $440,000

UQ ResTeach 2010-2012
ResTeach 2010 0.1 FTE School of Chemistry and Molecular Biosciences
Total value of grant: $26,900

NHMRC Career Development Award 2009-2012
Evolutionary events shaping the genome of Cryptococcus neoformans and their effects on pathogenesis
Total value of grant: $390,000

UQ Major Equipment and Infrastructure 2008
A high-throughput facility for the identification and analysis of gene regulatory elements and factors
Total value of grant: $160,000 (Co-Chief Investigators Melissa Brown, Bernie Carroll, Joe Rothnagel, Stuart Kellie, Ann Trezise, Rick Sturm, Andrew Perkins, Alan Cassady, Darren Trott, Jennifer Seddon, Matt Trau)

Teaching: 

BIOL2202 Genetics (Coordinator)

MICR2000 Microbiology & Immunology

MICR3001 Microbes & Human Health

Honours in Biochemistry & Molecular Biology (Coordinator)

Honours in Microbiology & Parasitology (Coordinator)

Selected Publications: