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Spatial and temporal regulation of the fungus-host interaction during life-threatening fungal infections

Final Report Summary - STRIFE (Spatial and temporal regulation of the fungus-host interaction during life-threatening fungal infections)

Fungal infections have a major impact on human health. Fungi cause irritating skin, mouth and vaginal infections, as well as life-threatening infections of the blood and organs in intensive care patients. The STRIFE programme investigated how a major fungal pathogen, Candida albicans, adapts and colonises host niches during disease progression.

Our experimental analyses of Candida-host interactions combined unbiased molecular exploration (to identify key processes that contribute to these interactions) with targeted molecular dissection (to characterise specific processes). Our analyses also depended on the development of ground-breaking technologies that permit: (a) the spatial dissection of Candida lesions from infected kidneys; (b) the 2D mapping of essential nutrients (e.g. iron) and specific proteins across infected organs; (c) the visualization of deep seated Candida infections with a new infra-red reporter; and (d) the rapid generation of Candida mutants with a refined molecular toolkit.

These new technologies, which are being distributed to our research community, have allowed us to make a series of exciting discoveries about the mechanisms by which Candida adapts to and infects the mammalian kidney.
1. We discovered that Candida infections trigger a tug-of-war between fungus and host over the essential element, iron. Candida infections perturb red blood cell recycling, leading to a build-up of iron in the kidney. Meanwhile localised defence mechanisms try to deprive the fungus of this iron. However, the fungus merely activates efficient scavenging mechanisms to scavenge sufficient iron.
2. We have contributed to the elaboration of mechanisms by which Candida adapts to changes in nutrient availability and host-imposed stresses. In particular, while most researchers examine fungal responses to individual environmental challenges, we have defined how Candida responds to the combinatorial challenges it faces in complex host niches. Our characterisation of fungal responses to physiologically relevant combinations of nutrients and host-imposed stresses is both novel and more relevant to infection.
3. We identified important differences between Candida albicans and the benign model yeast, Saccharomyces cerevisiae, in their regulation of central metabolism. These evolutionary differences allow Candida to grow on sugars and organic acids simultaneously (unlike Saccharomyces), and this enhances the ability of Candida to cause infections.
4. We found that as Candida adapts to changes in nutrient availability, this adaptation affects other fungal properties that enhance its ability to infect humans. Changes in nutrients not only trigger metabolic adaptation, they also affect the resistance of Candida to host-imposed stresses, fungal susceptibility to antifungal drugs, and the ability of our immune defences to recognise and clear Candida infections. This discovery has profound implications for the field of fungal immunology and therapy – as the fungus adapts to host niches it becomes a moving target that affects the efficacy of our immune defences and current antifungal therapies.

To summarise, the STRIFE programme has led the development of new technologies for the experimental dissection of fungal infections and provided novel insights into the dynamic interactions between fungus and host that underpin the development of life-threatening Candida infections. These include effective metabolic adaption to host niches, efficient scavenging of iron from these niches, robust responses to host-imposed stresses, and the avoidance of our immunological defences. So far, these discoveries have yielded 29 publications, and over 40 conference presentations and seminars. Five additional papers are in preparation.