An integrated transcriptomic and metabolomic approach to investigate the heterogeneous Candida albicans biofilm phenotype

Christopher Delaney; Bryn Short; Ranjith Rajendran; Ryan Kean; Karl Burgess; Craig Williams; Carol A Munro; Gordon Ramage

doi:10.1016/j.bioflm.2023.100112

An integrated transcriptomic and metabolomic approach to investigate the heterogeneous Candida albicans biofilm phenotype

Biofilm. 2023 Mar 12:5:100112. doi: 10.1016/j.bioflm.2023.100112. eCollection 2023 Dec.

Authors

Christopher Delaney¹, Bryn Short¹, Ranjith Rajendran¹, Ryan Kean², Karl Burgess³, Craig Williams⁴, Carol A Munro⁵, Gordon Ramage¹

Affiliations

¹ School of Medicine, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, UK.
² Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.
³ Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, Max Born Crescent, Edinburgh, UK.
⁴ Microbiology Department, Lancaster Royal Infirmary, University of Lancaster, Lancaster, UK.
⁵ School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, UK.

Abstract

Candida albicans is the most prevalent and notorious of the Candida species involved in bloodstream infections, which is characterised by its capacity to form robust biofilms. Biofilm formation is an important clinical entity shown to be highly variable among clinical isolates. There are various environmental and physiological factors, including nutrient availability which influence the phenotype of Candida species. However, mechanisms underpinning adaptive biofilm heterogeneity have not yet been fully explored. Within this study we have profiled previously characterised and phenotypically distinct C. albicans bloodstream isolates. We assessed the dynamic susceptibility of these differing populations to antifungal treatments using population analysis profiling in addition to assessing biofilm formation and morphological changes. High throughput methodologies of RNA-Seq and LC-MS were employed to map and integrate the transcriptional and metabolic reprogramming undertaken by heterogenous C. albicans isolates in response to biofilm and hyphal inducing serum. We found a significant relationship between biofilm heterogeneity and azole resistance (P < 0.05). In addition, we observed that in response to serum our low biofilm forming (LBF) C. albicans exhibited a significant increase in biofilm formation and hyphal elongation. The transcriptional reprogramming of LBF strains compared to high biofilm forming (HBF) was distinct, indicating a high level of plasticity and variation in stress responses by heterogenous strains. The metabolic responses, although variable between LBF and HBF, shared many of the same responses to serum. Notably, a high upregulation of the arachidonic acid cascade, part of the COX pathway, was observed and this pathway was found to induce biofilm formation in LBF 3-fold. C. albicans is a highly heterogenous bloodstream pathogen with clinical isolates varying in antifungal tolerance and biofilm formation. In addition to this, C. albicans is capable of highly complex and variable regulation of transcription and metabolic pathways and heterogeneity across isolates further increases the complexity of these pathways. Here we have shown with a dual and integrated approach, the importance of studying a diverse panel of C. albicans isolates, which has the potential to reveal distinct pathways that can harnessed for drug discovery.

Keywords: Biofilm; Candida albicans; Metabolomics; Transcriptomics.