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Pathogenomics and Systems Biology of Fungal Infections – An Integrative Approach

Final Report Summary - FINSYSB (Pathogenomics and Systems Biology of Fungal Infections – An Integrative Approach)

FINSysB - An interdisciplinary training in the Pathogenomics and Systems Biology of Fungal Infections

www.finsysb.eu

Potentially lethal fungal infections are having a major impact on the European population. They are harder to diagnose and treat than many bacterial infections, and their frequency is increasing. The socio-economic impact of fungal infections would be significantly reduced if clinicians had access to anti-Candida vaccines, more sensitive and accurate diagnostic tools, and a more comprehensive set of potent antifungal drugs. Therefore the FINSysB Network has addressed these urgent clinical needs, focusing the work programme on the best experimental model of fungal pathogenesis, Candida albicans, which is also the major cause of life-threatening fungal infections.

During this 4-year project, the FINSysB Network has: [1] Increased our understanding of host-fungus interactions during disease progression through a multidisciplinary research programme that combined state-of-the-art pathogenomics, immunology, molecular biology and systems biology; [2] Provided a superb interdisciplinary and cross-sectorial training for early stage and experienced researchers in fungal pathogenomics and systems biology; [3] Developed useful leads for novel anti-Candida vaccines, drugs and diagnostic markers with the help of commercial partners; and [4] Disseminated our work through publication in scientific journals (116 papers so far) seminars and international conferences (151 talks and 99 posters so far), and via a Public Outreach Programme that has included a YouTube video, Facebook, blogs and LinkedIn as well as the FINSysB website (www.finsysb.eu). All of our PhD graduates have gained postdoctoral positions in eminent laboratories.


The FINSysB Research Programme has investigated key aspects of host-fungus interactions during fungal infection through four interrelated research themes. First, we examined the ‘Pathogenic Armoury’ (i.e. fungal virulence and fitness attributes). Using a combination of experimental and predictive biology, we defined how C. albicans cells adapt to diverse and dynamic host microenvironments, activating stress responses following attack by immune defences and adjusting their metabolism to local nutrients. Local nutrients influence the cell wall architecture, stress and drug resistance and virulence of C. albicans. Second, in ‘Key Battlefields’, we identified new functions required for biofilm formation and for the regulation of biofilm formation and morphogenesis. We used high throughput screens with a new set of barcoded mutants that represents a valuable genomics resource for the research community. Also we identified genes required for cell wall integrity and the remodelling of the cell wall proteome in host microenvironments, thereby revealing new diagnostic and therapeutic targets. Third, in ‘Defensive Shields’ we showed how specific fungal triggers induce key immune pathways involved in the interplay between C. albicans and host immunity, most notably NF-kB, inflammasome and complement signalling. Morphogenesis was shown to play a key role in modulating the immune response of the host. We also highlighted specific mutations in immune signalling pathways that increase the susceptibility of patients to fungal infection. Fourth, in ‘Defeating the Enemy’ we identified and evaluated potential targets for novel vaccines, diagnostics and antifungal drugs. We identified recombinant antibodies with potential therapeutic and diagnostic utility, identified an exciting new antifungal target, and validated potent small molecular inhibitors that act on this target.

In this way the FINSysB Network has significantly advanced our understanding of host-fungus interactions during disease establishment and progression. Our Network has also generated a strong cohort of young scientists capable of driving European research forward in this medically important area.