Resource utilisation and the evolution of antifungal resistance in Candida species
Duxbury, Sarah Jennifer Nicola
Thesis or dissertation
University of Exeter
Reason for embargo
I wish to publish papers using material that is substantially drawn from my thesis.
Fungal pathogens, particularly species of the Candida genus, are responsible for superficial infections and invasive disease in humans, the latter of which is responsible for more deaths than tuberculosis or malaria. Despite this, fungal infections receive considerably less research attention than those of bacteria. Mixed-Candida species infections are increasing in prevalence, and occur as secondary infections in HIV and cancer patients. Resources are important in infection environments, in which competition between species and interactions with the host can influence community composition. After C. albicans, C. glabrata is the second most commonly isolated species, which colonises different host sites and patients and rapidly develops drug resistance. In this thesis, we investigate competition between C. albicans and C. glabrata in clinically-relevant in vitro cultures and in an invertebrate model. We then measure in vitro growth of C. glabrata strains over different glucose concentrations and the influence on virulence and antifungal adaptation. Following culture propagation in environments containing antifungal drug, we analyse C. glabrata fitness in evolved populations. We found that outcomes of short and long-term competition between C. albicans and C. glabrata were dependent on resource level in clinically-relevant media, with C. albicans favoured at low and C. glabrata favoured at high glucose (Chapter 2). C. glabrata clinical strains varied in competitive abilities (Chapter 2), and in their strength of interaction with C. albicans evidenced by differing levels of host survival in dual-species infections of the wax moth Galleria mellonella (Chapter 3). For growth on glucose, we identified a strain of C. glabrata (3605) isolated from a diabetic patient that had a significantly greater growth rate but lower final growth density than a lab reference strain (2001) (Chapter 4). We found that a higher growth density was correlated with greater virulence and adaptability to the antifungal caspofungin (Chapters 4 and 5). Finally, we found that caspofungin resistance could incur fitness costs and that sub-population variation in phenotypic adaptations evolved in parallel populations. These results improve understanding of microbial species interactions in infections by considering effects of resource levels and pathogen growth strategies on competitive abilities, virulence and antifungal resistance. This could lead to better characterisation of fungal infections and evolutionary adaptations in different host environments.
PhD in Biological Sciences