Objective The number of people who die from fungal infections is estimated to be equivalent to or greater than the numbers that die from either tuberculosis or malaria. There are only 3 classes of antifungal drugs available to treat these invasive diseases and resistance against these drugs is increasing. In this study I will investigate how antifungal resistance is impacted by cell heterogeneity in the pathogenic fungus Aspergillus fumigatus. The main hypothesis that I will test is that fungal cell heterogeneity provides subpopulations of cells with greater fitness to resist antifungal treatment. I will determine: (1) which features of three distinct fungal cell types contribute to cell heterogeneity; (2) which cell types and subpopulations of these cells show highest resistance or survival against antifungals; and (3) the roles of septal plugging and cell ploidy in the mechanistic basis of fungal cell heterogeneity. Cutting edge technologies that will be used in this study will include: (1) flow cytometry and fluorescence activated cell sorting (FACS) to identify and select cell subpopulations to test their antifungal resistance, (2) automated, high throughput, high content live cell imaging to analyse the resistance of single cells to antifungals, (3) advanced live-cell imaging techniques including GFP photoactivation and fluorescence recovery after photobleaching (FRAP) to identify septal pore plugging; and (4) laser microdissection to further analyse septal pore plugging. With these advanced techniques I will study the mechanistic basis of fungal resistance mediated by cell heterogeneity. My results will ultimately show how fungal cell heterogeneity impacts fitness against antifungal drugs and they will be the starting point for designing novel antifungal therapies that reduce this fitness. Fields of science medical and health scienceshealth sciencesinfectious diseasesmalariamedical and health sciencesbasic medicineimmunologymedical and health scienceshealth sciencesinfectious diseasesRNA virusesHIVmedical and health sciencesclinical medicinepneumologytuberculosisnatural sciencesbiological sciencesgeneticsepigenetics Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator THE UNIVERSITY OF MANCHESTER Net EU contribution € 195 454,80 Address Oxford road M13 9PL Manchester United Kingdom See on map Region North West (England) Greater Manchester Manchester Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 195 454,80