Role of antifungal drugs in modulating interaction between Candida glabrata and macrophages: cytokine profiles and TEM analysis.

Abstract

Candida glabrata often resides within macrophages, creating challenges for antifungal treatment. This study investigates the impact of antifungal agents on the immune response of C. glabrata within macrophages to understand its immune evasion mechanisms. Standard C. glabrata strains ATCC2001 and a clinical strain (17K1152) were pretreated with micafungin (MCF), itraconazole (ICZ), and amphotericin B (AmB) for 24 hours and then co-cultured with macrophages for 6, 12, 24, and 48 hours. Transmission electron microscopy (TEM) analysis was performed, and cytokine levels (interleukin [IL]-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) were measured using enzyme-linked immunosorbent assay kits. C. glabrata showed the greatest susceptibility to MCF, followed by AmB, with ICZ having the least effect. TEM analysis revealed MCF-induced damage to both the cell wall and membrane, whereas AmB disrupted only the membrane. ICZ showed less noticeable damage. MCF-pretreated yeast cells were more readily damaged in macrophages than those pretreated with AmB or ICZ. IL-6 secretion patterns were similar in untreated and ICZ-treated groups, while AmB initially decreased IL-6 secretion before recovery, and MCF consistently increased IL-6 levels. GM-CSF secretion showed comparable trends for untreated and ICZ groups, with MCF and AmB exhibiting fluctuations. Echinocandins enhanced macrophage immune activity by modifying C. glabrata's cell wall and increasing pro-inflammatory cytokine secretion, impairing its survival within host cells. Azole pretreatment had minimal impact on yeast replication and survival, reflecting resistance. Polyenes-treated yeast evade innate immunity by reducing pro-inflammatory cytokine secretion and modulating macrophage recruitment.IMPORTANCECandida glabrata is a major cause of bloodstream infections and is often resistant to antifungal treatment. Understanding how different antifungal drugs affect its survival within macrophages is critical for improving therapy. This study demonstrates that echinocandins enhance macrophage-mediated killing by damaging the fungal cell wall and increasing pro-inflammatory cytokine secretion, whereas azoles have minimal effect, and polyenes may aid immune evasion. These findings provide mechanistic insights into antifungal resistance and host-pathogen interactions, informing strategies for more effective treatment of C. glabrata infections.