Abstract
Candida albicans, a major opportunistic fungal pathogen, is frequently found together with Streptococcus mutans in dental biofilms associated with severe childhood caries (tooth decay), a prevalent pediatric oral disease. However, the impact of this cross-kingdom relationship on C. albicans remains largely uncharacterized. Here, we employed a novel quantitative proteomics approach in conjunction with transcriptomic profiling to unravel molecular pathways of C. albicans when cocultured with S. mutans in mixed biofilms. RNA sequencing and iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomics revealed that C. albicans genes and proteins associated with carbohydrate metabolism were significantly enhanced, including sugar transport, aerobic respiration, pyruvate breakdown, and the glyoxylate cycle. Other C. albicans genes and proteins directly and indirectly related to cell morphogenesis and cell wall components such as mannan and glucan were also upregulated, indicating enhanced fungal activity in mixed-species biofilm. Further analyses revealed that S. mutans-derived exoenzyme glucosyltransferase B (GtfB), which binds to the fungal cell surface to promote coadhesion, can break down sucrose into glucose and fructose that can be readily metabolized by C. albicans, enhancing growth and acid production. Altogether, we identified key pathways used by C. albicans in the mixed biofilm, indicating an active fungal role in the sugar metabolism and environmental acidification (key virulence traits associated with caries onset) when interacting with S. mutans, and a new cross-feeding mechanism mediated by GtfB that enhances C. albicans carbohydrate utilization. In addition, we demonstrate that comprehensive transcriptomics and quantitative proteomics can be powerful tools to study microbial contributions which remain underexplored in cross-kingdom biofilms.
Highlights
Candida albicans, a major opportunistic fungal pathogen, is frequently found together with Streptococcus mutans in dental biofilms associated with severe childhood caries, a prevalent pediatric oral disease
The multi-omics approach coupled with gene ontology (GO) pathway analysis and biochemical methods reveals that C. albicans has an active role in the sugar metabolism and environmental acidification when interacting with S. mutans
A quantitative proteomics approach coupled with RNA-Seq and systems analysis was employed to generate detailed molecular pathways associated with this cross-kingdom biofilm interaction, with a particular focus on the C. albicans counterpart, which remains underexplored in a cariogenic setting
Summary
A major opportunistic fungal pathogen, is frequently found together with Streptococcus mutans in dental biofilms associated with severe childhood caries (tooth decay), a prevalent pediatric oral disease. We identified key pathways used by C. albicans in the mixed biofilm, indicating an active fungal role in the sugar metabolism and environmental acidification (key virulence traits associated with caries onset) when interacting with S. mutans, and a new cross-feeding mechanism mediated by GtfB that enhances C. albicans carbohydrate utilization. Initial mechanistic studies revealed that S. mutans-derived GtfB binds firmly to the cell wall surface of C. albicans and produces large amounts of EPS ␣-glucans in the presence of sucrose [21, 22] These glucans serve as binding sites for S. mutans, promoting coadhesion and bacterial-fungal accumulation [21, 23]. The present study provides new insights into the synergistic cross-kingdom interaction between S. mutans and C. albicans within biofilms and a new cross-feeding role for GtfB in the context of ECC These findings indicate the importance of developing therapeutic strategies targeting fungal contributions and bacterial interactions associated with a prevalent childhood disease
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