Research Seminar: Feeding on the host: how do human fungal pathogens acquire essential trace metals during infection?
26 September 2018
Dr. Duncan Wilson, MRC Centre for Medical Mycology, The Institute of Medical Sciences, University of Aberdeen
Tuesday 2nd October, 1.00 p.m., Stacey Lecture Theatre 1
The mammalian immune system has evolved sophisticated mechanisms to withhold micronutrients such as zinc from potential invaders – a process known as nutritional immunity. In spite of this defence mechanism, pathogens still thrive and cause disease. Therefore, pathogenic microbes have, in turn, evolved mechanisms to circumvent nutritional immunity. Despite the fundamental importance of this host-pathogen "tug-of-war", its underlying mechanisms, and how they can be exploited to prevent disease remain poorly understood. We are exploring how pathogenic fungi adapt to fluctuations in zinc availability and how this essential, yet potentially toxic cation is mobilised within the fungal cell. Using Candida albicans as model fungal pathogen, we have discovered multiple assimilation strategies. For example, this fungus secretes a metal-binding protein (a "zincophore") to scavenges zinc from host tissue.
We have also developed intracellular fluorescent zinc probes and found that, following cellular internalisation, zinc is rapidly compartmentalised in zincosomes and within the fungal vacuole; these organellar compartmentalisation events are mediated by two distinct ZnT-type transporters. Zinc stores are then mobilised by Zip-type transporters when cells experience subsequent nutrient restriction. This mobilisation of organellar reserves alone is sufficient to promote growth. Using models of invasive candidiasis, we have shown that transporter management of intracellular zinc reservoirs significantly fuels the virulence of C. albicans.
This novel mechanism of counteracting nutritional immunity may have considerable clinical significance. This is because the pathogenic lifecycle of C. albicans involves translocation of the fungus from parts of the gastrointestinal tract, an environment of high zinc, to normally sterile internal organs.