Abstract
The fungal pathogen Candida albicans forms polymorphic biofilms where hyphal morphogenesis and metabolic adaptation are tightly coordinated by a complex intertwined network of transcription factors. The sensing and metabolism of amino acids play important roles during various phases of biofilm development – from adhesion to maturation. Stp2 is a transcription factor that activates the expression of amino acid permease genes and is required for environmental alkalinization and hyphal growth in vitro and during macrophage phagocytosis. While it is well established that Stp2 is activated in response to external amino acids, its role in biofilm formation remains unknown. In addition to widely used techniques, we applied newly developed approaches for automated image analysis to quantify Stp2-regulated filamentation and biofilm growth. Our results show that in the stp2Δ deletion mutant adherence to abiotic surfaces and initial germ tube formation were strongly impaired, but formed mature biofilms with cell density and morphological structures comparable to the control strains. Stp2-dependent nutrient adaptation appeared to play an important role in biofilm development: stp2Δ biofilms formed under continuous nutrient flow displayed an overall reduction in biofilm formation, whereas under steady conditions the mutant strain formed biofilms with lower metabolic activity, resulting in increased cell survival and biofilm longevity. A deletion of STP2 led to increased rapamycin susceptibility and transcriptional activation of GCN4, the transcriptional regulator of the general amino acid control pathway, demonstrating a connection of Stp2 to other nutrient-responsive pathways. In summary, the transcription factor Stp2 is important for C. albicans biofilm formation, where it contributes to adherence and induction of morphogenesis, and mediates nutrient adaption and cell longevity in mature biofilms.
Highlights
Candida albicans is the fungal species most frequently associated with the healthy human gastrointestinal, vaginal and skin microbiome
Nutrient sensing and utilization is important for C. albicans filamentation and biofilm formation, and mature biofilms are linked to activation of the tricarboxylic acid (TCA) cycle and amino acid metabolism
Since the transcription factor Stp2 controls utilization of extracellular amino acids, we investigated its role for biofilm establishment and maturation
Summary
Candida albicans is the fungal species most frequently associated with the healthy human gastrointestinal, vaginal and skin microbiome Under certain circumstances, such as immune suppression or disruptions of the associated microbiota, it can become pathogenic and infect virtually any part of the human body. Problematic is its ability to adhere to catheters and indwelling medical devices, such as artificial heart valves and joint replacements, and proliferate to form biofilms (Nobile and Johnson, 2015). These highly antibiotic-resistant, complex cell communities can serve as a reservoir of infection, since detached biofilm cells can disseminate to multiple body sites (Uppuluri et al, 2018), resulting in life-threatening diseases like sepsis. Candida spp. are consistently the third leading cause of device-associated bloodstream infections with mortality rate of up to 50% (Kojic and Darouiche, 2004)
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