The opportunistic human fungal pathogen Candida albicans displays a high degree of morphological plasticity, with the ability to switch between at least 7 different forms, depending on its environment. Of these, the hyphal form is able to penetrate host mucosal surfaces and therefore plays an important role in the dissemination and development of disease. Under certain conditions, including physical confinement and nutrient restriction, hyphae grow helically- a little-studied morphology which may afford the cell both increased virulence and drug resistance. This study investigates the molecular basis behind helical growth via both a large-scale screen and targeted analysis, through which we have uncovered the cooperation of diverse cellular processes, including cell wall and plasma membrane dynamics, whole-cell polarisation and calcium homeostasis. Furthermore, we have used a colon-on-chip model, which replicates the peristaltic stretch found in the human gut, to trigger 3D epithelial architecture, allowing the imaging and study of C. albicans hyphal invasion in situ. We have observed helical hyphal growth through gut epithelial layers, causing increased tissue damage in comparison with non-helical strains. This indicates for the first time that this morphology likely plays a role in tissue invasion. This model also sheds light on the involvement of gut peristalsis with prevention of systemic fungal infection. This work details a collaboration between diverse processes across the cell to produce a helical hypha morphology, which together aid human gut epithelial invasion.

Paris postdoc seminar series