Streptococcus mutans LiaS gene regulates its cross-kingdom interactions with Candida albicans to promote oral candidiasis

Candida albicans and Streptococcus mutans are commonly associated with oral candidiasis and dental caries, respectively. C. albicans is frequently detected in the dental plaque of early childhood caries. The synergistic interaction between C. albicans and S. mutans in dental caries suggests that fungi enhance the production of acidic metabolites and contributes to the development of caries. However, the cross-kingdom interaction of S. mutans in oral candidiasis and the pathways regulating hyphal formation remain unclear. The liaS gene of S. mutans 593 plays a crucial role in maintaining membrane homeostasis. In comparison to the S. mutans 593 and liaS- complementary strains, the liaS- strain significantly diminished the proliferation, biofilm formation, extracellular polysaccharide production, and C. albicans hyphal transformation of co-cultured microorganisms. The deletion of liaS gene in the dual-species downregulated the expression of yeast-hyphal transformation related genes hwp1, ece1, als1, and als3 in C. albicans, while also impacted the expression of phr1 and phr2. Additionally, liaS- inhibited glycolysis and pyruvate kinase activity in S. mutans, leading to a decreased in water-soluble and water-insoluble glucans production in biofilm. The significant downregulation of glucosyltransferase transcription relates genes expression in liaS- resulted in inhibition of the cross-kingdom interaction in the dual-species. In the murine oropharyngeal candidiasis model, dual-species infection with liaS- results in a reduction of fungal and hyphal invasion compared to the combinations of C. albicans and S. mutans 593. In conclusion, S. mutans/liaS play a crucial role in the development of oral candidiasis suggests that it could be a targeted strategy for managing this condition. ImportanceCandidiasis involves the transition of C. albicans into hyphae and the fungi invasion of the oropharyngeal mucosa. The transformation of hyphal is influenced by a variety of internal and external environmental factors. Our research findings suggest that the deletion of the liaS gene leads to a reduction in gtfs gene expression, impacting glycolysis efficiency and effectively decreasing EPS production in the dual-species biofilm. Also, downregulation of the expression levels of yeast-hyphal transformation related genes to inhibiting the virulence function of C. albicans. Our study demonstrates that S. mutans 593/liaS promotes epithelial invasion of C. albicans in mouse oropharyngeal candidiasis, offering a potential therapeutic approach for addressing cross-kingdom infections.