Immunological fitness of echinocandin-resistant Nakaseomyces glabratus (former Candida glabrata): The impact on the management of candidemia.

Nakaseomyces glabratus (formerly Candida glabrata) (N. glabratus) is a commensal yeast that is increasingly associated with invasive candidiasis. The rapid acquisition of echinocandin resistance by N. glabratus has raised public health concerns and led the WHO to classify it as a high-priority fungal pathogen in 2022. However, the impact of antifungal resistance on the host immune response remains poorly understood. Since echinocandin resistance often involves alterations to the fungal cell wall, which is critical for host immune recognition, such mutations may affect fungal fitness and immune evasion. We analyzed the immunological fitness of echinocandin-resistant N. glabratus, defined here as their capacity to modulate innate immune recognition, phagocytosis, and survival, using clinical isolates from a patient with recurrent bloodstream infections. In vitro yeast-macrophage and yeast-human leukocyte co-culture models were used to evaluate immune responses. Echinocandin-resistant isolates exhibited modified cell wall composition. Compared to susceptible strains, the resistant isolates induced altered kinetics of pro-inflammatory cytokine responses, predominantly involving TNF-α and demonstrated sustained survival within leukocyte aggregates in vitro. These results suggest that resistance-associated cell wall remodeling can influence host-pathogen interactions. These findings suggest that altered immune interactions and delayed clearance may confer additional fitness advantages to echinocandin-resistant N. glabratus, potentially impacting the pathophysiological interactions between host and pathogen.