Transcriptome Analysis Uncovers a Link Between Copper Metabolism, and Both Fungal Fitness and Antifungal Sensitivity in the Opportunistic Yeast Candida albicans

Inès Khemiri,Faiza Tebbji,Adnane Sellam

doi:10.3389/fmicb.2020.00935

Abstract

Copper homeostasis is an important determinant for virulence of many human pathogenic fungi such as the highly prevalent yeast Candida albicans. However, beyond the copper transporter Ctr1, little is known regarding other genes and biological processes that are affected by copper. To gain insight into the cellular processes that are modulated by copper abundance in C. albicans, we monitored the global gene expression dynamic under both copper depletion and excess using RNA-seq. Beyond copper metabolism, other different transcriptional programs related to fungal fitness such as stress responses, antifungal sensitivity, host invasion and commensalism were modulated in response to copper variations. We have also investigated the transcriptome of the mutant of the copper utilization regulator, mac1, and identified potential direct targets of this transcription factor under copper starvation. We also showed that Mac1 was required for the invasion and adhesion to host cells and antifungal tolerance. This study provides a framework for future studies to examine the link between copper metabolism and essential functions that modulate fungal virulence and fitness inside the host.

Highlights

The redox properties of copper (Cu) make this trace element crucial for biological systems as it serves as an essential cofactor of enzymes that function in many biological processes including iron acquisition, antioxidative defense, and energy metabolism (Festa and Thiele, 2011)
To gain insight into the cellular processes that are modulated by Cu abundance in the pathogenic yeast C. albicans, we monitored the global gene expression dynamic under both Cu depletion (400 μM Bathocuproinedisulfonic acid disodium salt (BCS)) and excess (2 mM CuSO4) using RNA-seq
Previous works have focused only on known Cu metabolic genes that are homologous to S. cerevisiae such as the Cu transporter Ctr1 (Marvin et al, 2004, 1), the transcription factor Mac1 (Woodacre et al, 2008) and the Cu efflux pump Crp1 (Weissman et al, 2000)

Summary

Introduction

The redox properties of copper (Cu) make this trace element crucial for biological systems as it serves as an essential cofactor of enzymes that function in many biological processes including iron acquisition, antioxidative defense, and energy metabolism (Festa and Thiele, 2011). For the highly prevalent human pathogenic yeast Candida albicans, Cu availability is highly dynamic for the same anatomical niche within the host. Upon earlier phase of kidney colonization, C. albicans is confronted by high levels of Cu which is considered as a host-imposed Cu-poisoning strategy (Mackie et al, 2016; Culbertson et al, 2020). This earlier Cu spike is followed by a rapid sequestration by renal tissues to probably limit fungal growth as C. albicans activates its own Cu utilization machinery to promote its fitness

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