Impact of fungal adaptation upon host recognition and pathogenesis

Fungal infections have a major impact on human health. Pathogenic (disease causing) fungi cause life-changing oral, genital and skin infections, and life-threatening systemic infections affecting internal organs. Most individuals carry the fungus Candida albicans in their microflora. Normally our immune system recognises invading Candida cells and kills them, thereby protecting us from infection. However, Candida infections arise when the efficiency of this immune surveillance is compromised. Hence this fungus is a frequent cause of irritating yeast infections such as "thrush". It also causes life-threatening bloodstream infections in weak and vulnerable patients, often undoing the excellent work done by cancer treatment and intensive care medicine. Indeed, in some patient groups, over 40% of these infections are fatal. As well as having a significant impact on human health, these infections have a significant economic impact. Despite the availability of reasonably effective antifungal drugs, bloodstream infections are estimated to extend the hospitalisation of patients by 22 days, increasing health care costs by over £20,000 per patient. As yet, no antifungal vaccines are available. Their development depends on an understanding of the mechanisms by which our immune system recognises and kills Candida cells. Significant progress has been made however. Research from a number of laboratories (including our own) has revealed that immune cells recognise specific types of molecule on the Candida cell surface as "foreign". After recognising these molecules ("pathogen-associated molecular patterns"), the immune cells generally swallow the Candida cells (a process called "phagocytosis"), and then kill them by subjecting the fungus to a battery of toxic chemicals, thereby clearing the infection. This generally accepted view is based largely on experiments involving Candida albicans cells grown in the laboratory under well-defined culture conditions on specific growth media, and not cells grown in an infected host. Unfortunately, these laboratory growth media differ significantly from the conditions that Candida experiences during an infection. We have shown recently that changes in growth conditions significantly affect: (a) the architecture of the Candida cell surface; (b) recognition by our immune system; and (c) Candida's capacity to cause disease. Therefore our hypothesis is that during the onset and progression of an infection, Candida cells encounter and adapt to changes in host niches, thereby affecting their growth. This affects the expression and exposure of "pathogen-associated molecular patterns" on the fungal cell surface. We predict that these changes strongly influence the effectiveness of local immune surveillance, allowing more fungal cells to survive these host defences, thereby influencing disease progression and the outcome of the infection. In other words, fungal physiology resists host immunology. The over-arching goal of our research programme is to test this hypothesis by defining the effects of Candida adaptation mechanisms upon the efficacy of immune surveillance and infection outcome. With the help of the three postdoctoral researchers, plus two PhD students provided by Aberdeen University, we will achieve this by combining our synergistic expertise in the analysis of Candida albicans nutrient and stress adaptation, the Candida cell surface, Candida pathogen-associated molecular patterns and immune recognition, the dynamics of phagocytosis and fungal killing, and Candida infection biology. We will integrate well-established molecular approaches with powerful new genomic technologies and state-of-the-art cellular imaging (many of which were developed in our labs). This research is essential if we are to properly understand anti-Candida immunity in the context of disease onset and progression. This knowledge will facilitate the development of effective anti-Candida vaccines and novel immunotherapies.