FUNFIT · Fungal resistance to antifungals is promoted by cell heterogeneity

Fungal resistance to antifungals is promoted by cell heterogeneity

Problem The main hypothesis that I will test is that fungal cell heterogeneity provides subpopulations of cells with greater fitness to resist antifungal treatment. Importance for society The number of people who die from fungal infections (~2 million p.a.) is greater than the numbers that die from tuberculosis or malaria (1.3 and 0.63 million p.a., respectively). Furthermore, ~25% of the world’s population at any one time suffer from superficial fungal infections of skin and nails. The lung disease aspergillosis, caused by Aspergillus fumigatus, is one of the most common invasive fungal diseases and mortality rates are nearly 100% when untreated and as high as 50% when treated. Individuals most susceptible to invasive fungal diseases are those that are immunocompromised (e.g. patients with AIDS or undergoing immunosuppressive drug treatment). There are only 3 major classes of commercial antifungal drugs available to treat invasive fungal diseases: azoles (which inhibit ergosterol synthesis), polyenes (which target ergosterol in the plasma membrane), and echinocandins (which inhibit β-1,3-glucan synthesis in the cell wall). Resistance of A. fumigatus and other fungal pathogens against antifungal drugs is increasing. This is particularly significant with regard to the azoles that are the first-line treatment of invasive fungal diseases. A significant cause of this has been attributed to the widespread agricultural use of azole fungicides. Different resistance mechanisms against azoles and other antifungals have been reported including: exclusion or active efflux from the fungal cell; overproduction of the drug target; and structural alterations of the drug target by mutations. A mechanistic understanding of antifungal resistance and discovery of new antifungals is of critical importance to combat the very serious problem of invasive fungal diseases. Objectives (1) Determine which features of three distinct fungal cell types contribute to cell heterogeneity; (2) Determine which cell types and subpopulations of these cells show highest resistance or survival against antifungals; and (3) Determine the roles of septal plugging and cell ploidy in the mechanistic basis of fungal cell heterogeneity. Conclusions (1) Cell heterogeneity can be observed in different cell types and for many different characteristics of cells (e.g. cell wall composition) (2) Cell heterogeneity is dynamic, but persistent in successive cell generations (3) My data suggests that cell heterogeneity impacts antifungal treatment (4) Cell heterogeneity influences phagocytosis of spores by immune cells (macrophages) (5) Our data provides evidence that epigenetics are involved in the emergence of cell heterogeneity

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз