Sodium houttuyfonate enhances the mono-therapy of fluconazole on oropharyngeal candidiasis (OPC) through HIF-1α/IL-17 axis by inhibiting cAMP mediated filamentation in Candida albicans-Candida glabrata dual biofilms

Candida albicans and Candida glabrata are two common opportunistic fungi that can be co-isolated in oropharyngeal candidiasis (OPC). Hypha is a hallmark of the biofilm formation of C. albicans, indispensable for the attachment of C. glabrata, which is seldom in mycelial morphology. Increasing evidence reveals a hypoxic microenvironment in interior fungal biofilms, reminding of a fact that inflammation is usually accompanied by oxygen deprivation. As a result, it is assumed that the disaggregation of hypha-mediated hypoxia of biofilms might be a solution to alleviate OPC. Based on this hypothesis, sodium houttuyfonate (SH), a well-identified traditional herbal compound with antifungal activity, is used in combination with fluconazole (FLU), a well-informed synthesized antimycotics, to investigate their impact on filamentation in C. albicans and C. glabrata dual biofilms and the underlying mechanism of their combined treatment on OPC. The results show that compared with the single therapy, SH plus FLU can inhibit the hyphal growth in the mixed biofilms in vitro, decrease the fungal burden of oral tissues and internal organs, restore mucosal epithelial integrity and function, and reduce hypoxic microenvironment and inflammation in a mice OPC model. The possible mechanism of the combined therapy of SH plus FLU can be attributed to the regulation of HIF-1α/IL-17A axis through direct abrogation of the dual Candida biofilm formation. This study highlights the role of HIF-1α/IL-17A axis and the promising application of SH as a sensitizer of conventional antifungals in the treatment of OPC.