Frontiers in medicine · 2026
The roles of SAP2, STP1, and MRR2 on biofilm formation and itraconazole resistance through autophagy in Candida albicans.
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Yang Jing, Feng Wenli, Xie Mingjun, Yu Daiyao, Yang Wenqin, Ma Yan, Xi Zhiqin
Аннотация
BACKGROUND: Candida albicans biofilm formation and azole antifungal resistance are major obstacles to clinical treatment of candidiasis. STP1 and MRR2 are implicated in C. albicans virulence and stress responses, while SAP2 plays critical roles in biofilm formation and drug resistance. However, the regulatory mechanisms of STP1 and MRR2 on SAP2 expression, biofilm formation, and itraconazole (ITR) resistance, particularly via autophagy, remain unclear.
METHODS: We compared biofilm-forming ability (via crystal violet assay and microscopy), ITR susceptibility, and autophagic responses among standard ATCC11006, STP1∆/∆, MRR2∆/∆, ITR-sensitive, and ITR-resistant strains. Gene expression levels of SAP2, and key autophagy-related genes were quantified using RT-qPCR under planktonic and biofilm conditions. The role of autophagy was further investigated using the inducer rapamycin and nitrogen starvation assays.
RESULTS: ITR-resistant strains exhibited significantly stronger biofilm-forming ability than sensitive strains. STP1 deletion enhanced biofilm formation, while MRR2 deletion impaired it. SAP2, STP1, and MRR2 expression was significantly higher in resistant strains than in sensitive strains under both planktonic and biofilm states, with a significant positive correlation between SAP2 and MRR2 under planktonic conditions (r = 0.659, p = 0.002). Notably, expression of all tested autophagy-related genes was significantly upregulated in biofilms and in ITR-resistant strains, but was markedly downregulated in both STP1Δ/Δ and MRR2Δ/Δ strains. Rapamycin induced autophagosome formation and upregulated SAP2 and ATG gene expression, but this response was blunted in the knockout strains. Furthermore, both STP1Δ/Δ and MRR2Δ/Δ strains displayed increased sensitivity to nitrogen starvation.
CONCLUSION: Our findings demonstrate that STP1 and MRR2 are critical regulators of biofilm formation and ITR resistance in Candida albicans. They exert these effects, at least in part, by modulating the expression of SAP2 and, importantly, by governing the autophagic pathway.
METHODS: We compared biofilm-forming ability (via crystal violet assay and microscopy), ITR susceptibility, and autophagic responses among standard ATCC11006, STP1∆/∆, MRR2∆/∆, ITR-sensitive, and ITR-resistant strains. Gene expression levels of SAP2, and key autophagy-related genes were quantified using RT-qPCR under planktonic and biofilm conditions. The role of autophagy was further investigated using the inducer rapamycin and nitrogen starvation assays.
RESULTS: ITR-resistant strains exhibited significantly stronger biofilm-forming ability than sensitive strains. STP1 deletion enhanced biofilm formation, while MRR2 deletion impaired it. SAP2, STP1, and MRR2 expression was significantly higher in resistant strains than in sensitive strains under both planktonic and biofilm states, with a significant positive correlation between SAP2 and MRR2 under planktonic conditions (r = 0.659, p = 0.002). Notably, expression of all tested autophagy-related genes was significantly upregulated in biofilms and in ITR-resistant strains, but was markedly downregulated in both STP1Δ/Δ and MRR2Δ/Δ strains. Rapamycin induced autophagosome formation and upregulated SAP2 and ATG gene expression, but this response was blunted in the knockout strains. Furthermore, both STP1Δ/Δ and MRR2Δ/Δ strains displayed increased sensitivity to nitrogen starvation.
CONCLUSION: Our findings demonstrate that STP1 and MRR2 are critical regulators of biofilm formation and ITR resistance in Candida albicans. They exert these effects, at least in part, by modulating the expression of SAP2 and, importantly, by governing the autophagic pathway.