Candida albicans Extracellular Vesicles Upregulate Nrg1 Transcription Repressor to Inhibit Self-Hyphal Development and Candidemia

Candida albicans is the most prevalent opportunistic pathogenic fungus in humans, and its extracellular vesicles (EVs) play crucial roles in its growth and pathogenesis. Previously, we found that C. albicans EVs at low levels could promote its growth. However, the effects of EVs when accumulated at high concentrations in C. albicans remain unclear. This study revealed that a high concentration of EVs inhibited hyphal development in C. albicans in a time-dependent manner. Transcriptome and RT-qPCR analyses showed that EVs significantly upregulated the transcription repressor NRG1 and downregulated hyphal-specific genes in a laboratory strain and five clinical isolates, while EVs failed to repress nrg1Δ/Δ hyphae. Further experiments confirmed that EVs upregulated the upstream transcription factor SKO1 (but downregulated BRG1) to increase NRG1 expression, thereby inhibiting hyphal formation. Cargo proteins in EVs were key components that inhibited C. albicans hyphal growth. Additionally, EV-treated C. albicans showed improved mouse survival and reduced organ fungal burden in candidemia, but EVs did not attenuate virulence in nrg1Δ/Δ-infected mice. These results reveal that C. albicans EVs at high levels play an important role in its pathogenicity and highlight the potential for novel therapeutic strategies.