See the PhD Opportunities section to see if this project is currently open for applications via MIBTP.
Please Note: The main page lists projects via BBSRC Research Theme(s) quoted and then relevant Topic(s).
How membrane lipids and oxygen shape fungal growth and host invasion
Secondary Supervisor(s): Prof Rebecca Drummond
University of Registration: University of Birmingham
BBSRC Research Themes:
Project Outline
Fungal infections kill millions of people each year. Among the most difficult are the Mucorales, which cause mucormycosis in people with diabetes or compromised immunity, with mortality frequently exceeding 50%.
Mucorales are dimorphic, switching between yeast-like and filamentous growth in response to oxygen and carbon dioxide. The two forms do different things: hyphae invade tissue, whereas yeast-like cells proliferate and disperse. The signalling behind the switch is well described, but how the cell executes it is not.
Building a hypha demands sustained membrane delivery to a small, highly curved apex. That apex requires a specific lipid environment, built from sterols and unsaturated fatty acids, neither of which can be made without molecular oxygen. Does oxygen availability therefore constrain which geometries a fungus can build?
Aims:
Determine how membrane composition, organisation and mechanics change as Mucor transitions between yeast-like, germling and hyphal forms across defined oxygen tensions, and how oxygen affects both the lipids produced and their transport to the growing apex.
Establish whether membrane biophysics constrains morphological switching. Manipulate sterol and fatty acid metabolism (genetically and phamacologically) to test whether altering membrane properties changes the ability of cells to build and maintain polarised growth, and whether this acts independently of calcineurin. Combine imaging with modelling to relate lipid composition, curvature and cell shape.
Determine how oxygen availability constrains polarised growth during infection. Test whether spores pre-conditioned under low oxygen show reduced apical membrane organisation and delayed germ tube formation after phagocytosis by primary macrophages, in vitro and in vivo using the peritoneal model. Compare fungal morphology between organs with contrasting oxygen exposure, such as lung and kidney medulla, using lipid metabolism mutants from Aim 2 where available.