Queen’s DTP: The genetic and/or epigenetic nature of antifungal drug tolerance in Candida glabrata

This project opportunity is offered as part of the Queen's Doctoral Training Programme - Multi-dimensional approaches to understanding microbe/host interactions in the context of disease, therapeutics and community resilience. For more information, please visit: https://www.findaphd.com/phds/program/queen-s-doctoral-training-programme-multi-dimensional-approaches-to-understanding-microbe-host-interactions-in-the-context-of-disease-therapeutics-and-community-resilience/?p4840

The pathogenic fungi Candida albicans and Candida glabrata are obligate human commensals that can cause disease when host immune systems are compromised. Treating such infections has become increasingly more challenging due to the rise in antifungal resistance. It has been recently discovered that Candida species can generate sub-populations of specialized antifungal tolerant cells when exposed to lethal concentrations of antifungal drugs(1). It is thought that this drug tolerant state provides an opportunity for such cells to acquire the necessary genetic mutation to become antifungal resistant (2). Furthermore, such drug tolerant cells are readily isolated from patients with recurrent Candida infections (3).

However, very little is known about the establishment or maintenance of drug tolerance in Candida. This project aims to characterize the tolerant state in the clinically relevant yeast, Candida glabrata, and determine whether it is determined by genetic and/or epigenetic mechanisms.

Initially we will investigate the frequency, reproducibility and stability of the drug tolerant state under different antifungal drug regimes. We will compare wild-type (WT) C. glabrata with genetically modified strains that lack epigenetic regulators, such as histone acetyl-transferases and histone deacetylases. Next, state-of-the-art DNA and RNA sequencing technologies will be used to interrogate the genomes and transcriptome of drug tolerant cells respectively. In collaboration with the Wallace lab at the University of Edinburgh, we will analyse these datasets to identify molecular signatures of drug tolerance. We will also take a Systems Biology approach to model the stochastic establishment of drug tolerance, and how this random process depends on epigenetic regulators. These analyses will further our understanding of the biological variables that contribute to antifungal tolerance in C. glabrata.

Candidate requirements:

Undergraduate degree in Microbiology, Molecular Biology, Biomedical Science, or Biochemistry.

Skills required: Computational/numerical literacy and eagerness to learn bioinformatics. Aseptic technique.

Skills desired: Molecular biology laboratory skills. Bioinformatics or data analysis skills (Unix/R/Python).

Start date: October 2021

Duration: 3.5 years

How to apply:

Applicants for this project must apply to the School of Biological Sciences PhD programme at Queen’s via https://dap.qub.ac.uk/portal/user/u_login.php