Abstract
The fungal pathogen Candida albicans is a common cause of opportunistic infections in humans. We report that wild-type Drosophila melanogaster (OrR) flies are susceptible to virulent C. albicans infections and have established experimental conditions that enable OrR flies to serve as model hosts for studying C. albicans virulence. After injection into the thorax, wild-type C. albicans cells disseminate and invade tissues throughout the fly, leading to lethality. Similar to results obtained monitoring systemic infections in mice, well-characterized cph1Δ efg1Δ and csh3Δ fungal mutants exhibit attenuated virulence in flies. Using the OrR fly host model, we assessed the virulence of C. albicans strains individually lacking functional components of the SPS sensing pathway. In response to extracellular amino acids, the plasma membrane localized SPS-sensor (Ssy1, Ptr3, and Ssy5) activates two transcription factors (Stp1 and Stp2) to differentially control two distinct modes of nitrogen acquisition (host protein catabolism and amino acid uptake, respectively). Our results indicate that a functional SPS-sensor and Stp1 controlled genes required for host protein catabolism and utilization, including the major secreted aspartyl protease SAP2, are required to establish virulent infections. By contrast, Stp2, which activates genes required for amino acid uptake, is dispensable for virulence. These results indicate that nutrient availability within infected hosts directly influences C. albicans virulence.
Highlights
Due to growing numbers of immune-compromised individuals, fungal infections in humans are becoming an increasing concern [1,2,3]
To determine if wild-type Drosophila could be used for C. albicans virulence studies, the common laboratory strain OrR was injected with different concentrations of wild-type C. albicans cells and survival was compared to those flies injected with phosphate-buffered saline (PBS) (Figure 1B and Table S1)
We noted that lethality was dependent on the use of C. albicans cells grown to log-phase (OD600 < 1); flies are less susceptible to infection when stationary phase cells are injected
Summary
Due to growing numbers of immune-compromised individuals, fungal infections in humans are becoming an increasing concern [1,2,3]. Candida albicans is principally responsible for the increased incidence of fungal infections, and is currently the fourth most common cause of septicemia in developed countries [4,5,6]. Information regarding basic fungal biology and virulence traits is critical to facilitate the development of novel treatment strategies. In contrast to many microbial pathogens, C. albicans has a diverse metabolic repertoire and is able to colonize virtually any tissue and organ [8,9], where it grows in yeast-like, pseduohyphal and hyphal forms; little is known regarding what nutrients are utilized during infectious growth. A required nutrient is nitrogen, which is readily available in two forms in infected hosts, amino acids and proteins. C. albicans cells possess the means to utilize both of these forms of nitrogen [10]
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