Streptococcus mutans sigX-inducing peptide inhibits the virulence of Candida albicans and oral candidiasis through the Ras1-cAMP-Efg1 pathway

Abstract

Oral candidiasis is the most common fungal infectious disease in the human oral cavity, and Candida albicans is the major pathogenic agent. Increasing drug resistance and the lack of new types of antifungals greatly increase the challenges for treating fungal infections. Targeting hyphal transition provides a promising strategy to inhibit the virulence of C. albicans and overcome drug resistance. This study aimed to investigate the effects and mechanisms of sigX-inducing peptide (XIP), a quorum-sensing signal peptide secreted by Streptococcus mutans, on C. albicans hyphal development and biofilm formation in vitro and oropharyngeal candidiasis in vivo. XIP significantly inhibited C. albicans yeast-to-hypha transition and biofilm formation in a dose-dependent manner from 0.01 to 0.1 µM. XIP significantly downregulated expression of genes from the Ras1-cAMP-Efg1 pathway (RAS1, CYR1, TPK2, EFG1 and UME6), a key pathway to regulate C. albicans hyphal development. Importantly, XIP reduced the levels of key molecules cAMP and ATP from this pathway, while the addition of exogenous cAMP and overexpression of RAS1 restored the hyphal development inhibited by XIP. XIP also lost its hyphal inhibitory effects on ras1Δ/Δ and efg1Δ/Δ strains. These results further confirmed that XIP inhibited hyphal development through downregulation of the Ras1-cAMP-Efg1 pathway. A murine oropharyngeal candidiasis model was employed to evaluate the therapeutic effects of XIP on oral candidiasis. XIP effectively reduced the infected epithelial area, fungal burden, hyphal invasion and inflammatory infiltrates. These results revealed the antifungal effects of XIP, and highlighted that XIP can be a potential antifungal peptide against C. albicans infection.

Keywords: Candida albicans; Interkingdom interaction; Oral candidiasis; Ras1-cAMP-Efg1 pathway; Streptococcus mutans; sigX-inducing peptide.