Distinct metabolic states of yeast and pseudohyphae differentially prime innate immune responsiveness

Abstract

Pseudohyphal growth in skin-associated fungi is often considered a morphological response to environmental stress, but whether it represents a coordinated metabolic state that influences host immunity remains unclear. Using Malassezia furfur, we combined synchronized morphogenesis, temporal metabolomics, stable-isotope tracing, targeted metabolite measurements, transcriptional profiling, and functional immune assays to compare yeast and pseudohyphal states. Yeast cells maintained an active tryptophan-aldehyde metabolic program that partitioned carbon between oxidative and reductive branches associated with redox balance and methylation potential. Pseudohyphal cells attenuated this program and instead underwent sequential metabolic remodeling, characterized by early changes in one-carbon and amino acid metabolism followed by sulfur-pathway remodeling and increased glutathione biosynthesis. These distinct fungal states generated extracellular environments that altered THP-1 innate immune responsiveness without directly inducing canonical macrophage polarization. Yeast-conditioned cells responded preferentially to tissue-repair signals, whereas pseudohypha-conditioned cells displayed enhanced responses to inflammatory stimuli. Individual metabolites did not reproduce these effects, suggesting that immune conditioning depends on the integrated extracellular milieu. Together, these findings identify pseudohyphal growth as an organized adaptive metabolic state and establish a framework linking fungal morphogenetic potential to context-dependent host immune responses.