Dr Megan Lenardon

Opportunistic invasive fungal pathogens cause over two million life-threatening infections per year worldwide, with mortality ranging from 20–95%. The number of deaths per year is greater than those attributed to either malaria, or breast cancer or prostate cancer. Bloodstream infections caused by Candida species (candidaemia) are the most frequent life-threatening invasive fungal infections, with the majority caused by one species, Candida albicans.

C. albicans colonises the gut of most healthy individuals but does not usually cause serious disease because the physical barriers between our gut and the bloodstream, combined with our immune defences and the suppressive powers of the indigenous gut microbiota, prevent these infections. However, this opportunistic pathogen can cause serious, life-threatening disseminated disease when these barriers and defences are compromised (e.g. seriously ill patients in the ICU, during cancer chemotherapy or immunotherapy, organ/stem cell transplantation, or when the gut microbiota is disturbed), which renders us vulnerable to infections from the C. albicans that colonises our gut. Despite the availability of antifungal drugs, over 40% of these systemic infections are fatal in certain patient groups. There is an urgent clinical need for the development of diagnostics and new therapies for invasive candidiasis which research in my group aims to address in innovative ways.

Cell wall structure and biosynthesis. I have been studying the cell and molecular biology of C. albicans for over 18 years and have developed specific expertise in the biosynthesis of the C. albicans cell wall and its structure. My postdoctoral research was focussed on the regulation of the synthesis of chitin, an essential structural polysaccharide found in the cell wall almost all pathogenic fungi, but is not found in humans, and so represents an attractive target for antifungal drugs. Utilising state-of-the-art imaging techniques, I have investigated the precise ultrastructure of the C. albicans cell wall. These methods include high pressure freezing/freeze substitution, transmission electron microscopy and electron tomography. Determining precisely how the cell wall components are arranged, and how their arrangement changes as cells encounter different conditions, has informed the understanding of the innate and adaptive immune responses to fungi.

Gut fungi. Utilising a novel in vitro system which mimics conditions in the human colon, projects in this area are aimed at advancing our understanding of the mechanisms by which C. albicans adapts to and evolves in a key host niche, how this adaptation can be compromised by natural bacterial and fungal components of certain healthy GI microbiotas, and how this can be exploited to prevent C. albicans infections arising from the GI tract. Projects are also aimed at generating a better understanding of composition and functional role of the entire fungal component of the GI microbiota.

Development of antifungal polymers. In collaboration with Prof. Cyrille Boyer in the School of Chemical Sciences and Engineering at UNSW, a library of polymers which resemble antimicrobial peptides with antifungal activity has been synthesised, tested and optimised. With collaborators at the Hans Knoell Institute in Jena, Germany, the mode of action of these new antifungal polyacrylamides is being investigated.

Cell division and septation in fungi. Drawing largely on my expertise in fungal cell wall biology, I have investigated the fundamental process of septation with a view to undermining cell division as an attractive way to conquer disease by pharmacological intervention. Projects in this area were aimed at understanding how chitin is synthesised at septation sites and how this process is regulated.

Antibody-based therapies and diagnostics for fungal infections. Antibodies that recognise components of the fungal cell surface may provide bio-tools for the development of diagnostic and therapeutic agents with utility against fungal infections. They may also provide a much-needed alternative to the current inadequate range of chemical-based antifungal drugs. Projects in this area were aimed at demonstrating the therapeutic and diagnostic utility of monoclonal antibodies which recognise fungal cell wall polysaccharides.