Candida albicans PPG1, a serine/threonine phosphatase, plays a vital role in central carbon metabolisms under filament-inducing conditions: A multi-omics approach.

Mohammad Tahseen A L Bataineh,Muath Khairi Mousa,Mawieh Hamad,Nihar Ranjan Dash,Luiz F Zerbini,Mutaz F Al Gharaibeh,Nelson Cruz Soares,Jasmin Shafarin Abdul Salam,Mohamad Hamad,Mohammad Harb Semreen,Stefano Cacciatore,Yong-Sun Bahn

doi:10.1371/journal.pone.0259588

Abstract

Candida albicans is the leading cause of life-threatening bloodstream candidiasis, especially among immunocompromised patients. The reversible morphological transition from yeast to hyphal filaments in response to host environmental cues facilitates C. albicans tissue invasion, immune evasion, and dissemination. Hence, it is widely considered that filamentation represents one of the major virulence properties in C. albicans. We have previously characterized Ppg1, a PP2A-type protein phosphatase that controls filament extension and virulence in C. albicans. This study conducted RNA sequencing analysis of samples obtained from C. albicans wild type and ppg1Δ/Δ strains grown under filament-inducing conditions. Overall, ppg1Δ/Δ strain showed 1448 upregulated and 710 downregulated genes, representing approximately one-third of the entire annotated C. albicans genome. Transcriptomic analysis identified significant downregulation of well-characterized genes linked to filamentation and virulence, such as ALS3, HWP1, ECE1, and RBT1. Expression analysis showed that essential genes involved in C. albicans central carbon metabolisms, including GDH3, GPD1, GPD2, RHR2, INO1, AAH1, and MET14 were among the top upregulated genes. Subsequent metabolomics analysis of C. albicans ppg1Δ/Δ strain revealed a negative enrichment of metabolites with carboxylic acid substituents and a positive enrichment of metabolites with pyranose substituents. Altogether, Ppg1 in vitro analysis revealed a link between metabolites substituents and filament formation controlled by a phosphatase to regulate morphogenesis and virulence.

Highlights

Candida albicans is the most common opportunistic fungal pathogen in humans
The pattern of gene expression in wild-type (DK318) and ppg1Δ/Δ (MAY34) strains of C. albicans growing under filament-inducing (10% fetal bovine serum at 37 ̊C) at different time points post culture (3 and 5 hours) was investigated as means of tracking any transcriptional changes that occur during the morphological transition from yeast to hyphae
The filamentation phenotype of both wild-type (W.T.) and ppg1Δ/Δ C. albicans strains under filamentation induction conditions was confirmed microscopically and was consistent with previously published observations [28]

Summary

Introduction

Candida albicans is the most common opportunistic fungal pathogen in humans. It causes mucosal and systemic infections and is of medical significance due to its ability to cause hospital-acquired bloodstream infections with high mortality [1,2]. A significant virulence property is the ability to undergo a dimorphic shift from single oval-shaped cells (yeast) into elongated cells attached end-to-end (pseudohyphal and hyphal filaments) in response to host environmental conditions [8,9,10]. Various host environmental stimuli induce C. albicans yeast-hyphal transition through a coordinated expression of transcriptional regulators influencing multiple signal transduction pathways, including the MAP kinase pathway and the Ras-cAMP-Protein Kinase A (PKA) pathway, among others [17]. The contribution of phosphatases in fungal stress responses remains ambiguous

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