Abstract
Candida albicans is an opportunistic human fungal pathogen that relies upon different virulence traits, including morphogenesis, invasion, biofilm formation, and nutrient acquisition from host sources as well as metabolic adaptations during host invasion. In this study, we show how sugar kinases at the start of glycolysis modulate virulence of C. albicans. Sequence comparison with Saccharomyces cerevisiae identified four enzymes (Hxk1, Hxk2, Glk1, and Glk4) in C. albicans with putative roles in sugar phosphorylation. Hxk2, Glk1, and Glk4 demonstrate a critical role in glucose metabolism, while Hxk2 is the only kinase important for fructose metabolism. Additionally, we show that Hxk1 controls HXK2, GLK1, and GLK4 expression in the presence of fermentable as well as non-fermentable carbon sources, thereby indirectly controlling glycolysis. Moreover, these sugar kinases are important during virulence. Disabling the glycolytic pathway reduces adhesion capacity, while deletion of HXK1 decreases biofilm formation. Finally, we demonstrate that hxk2Δ/Δ glk1Δ/Δ glk4Δ/Δ and hxk1Δ/Δ hxk2Δ/Δ glk1Δ/Δ glk4Δ/Δ have attenuated virulence upon systemic infections in mice. These results indicate a regulatory role for Hxk1 during sugar phosphorylation. Furthermore, these kinases are essential during growth on glucose or fructose, and C. albicans relies on a functional glycolytic pathway for maximal virulence.
Highlights
Candida albicans is an opportunistic fungal pathogen
We hypothesized that the deletion of one or multiple kinases would affect the growth of C. albicans on glucose and fructose containing media, due to a possible reduced glycolytic flux
For growth on 2% of glucose, hxk2, hxk1 hxk2 and hxk2 glk1 glk4 showed a reduced growth compared to the wild type (WT) (Figure 1A)
Summary
Candida albicans is an opportunistic fungal pathogen. It is the predominant causal agent of invasive candidiasis and the fourth leading cause of hospital-acquired infections (Perlroth et al, 2007). Candida albicans virulence traits are under tight control of different signaling pathways, including the external pH-regulated Rim101 pathway, the protein kinase A (PKA) pathway, and the mitogen-activated protein kinase (MAPK) pathway These last two are important for growth, morphogenesis, and adhesion (Davis, 2003; Biswas et al, 2007; Han et al, 2011). Enzymes involved in the glucose repression mechanism have an effect on virulence, since two transcription factors, Mig and Mig, involved in this pathway have a dual role They inhibit the expression of genes necessary for the utilization of alternative carbon sources, and they are responsible for the expression of genes involved in virulence traits, like filamentation and biofilm formation (Lagree et al, 2020). We demonstrate that the hxk2 / glk1 / glk4 / and the hxk1 / hxk2 / glk1 / glk4 / mutants are avirulent during a systemic infection in mice
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