Vacuolar sterol β-glucosidase EGCrP2/Sgl1 deficiency in Cryptococcus neoformans: Dysfunctional autophagy and Mincle-dependent immune activation as targets of novel antifungal strategies

• DOI: 10.1371/journal.ppat.1013089
• Publication Date: 2025-04-24T17:41:03Z
• Authors: Takashi Watanabe; Masayoshi Nagai; Yohei Ishibashi; Mio Iwasaki; Masaki Mizoguchi; Masahiro Nagata; Takashi Imai; Koichi Takato; Akihiro Imamura; Yoshimitsu Kakuta; Takamasa Teramoto; Motohiro Tani; Junko Matsuda; Hideharu Ishida; Sho Yamasaki; Nozomu Okino; Makoto Ito
• Keywords: Virulence factor; Antifungal drugs

Cryptococcus neoformans ( Cn ) is a fungal pathogen responsible for cryptococcal meningitis, which accounts 15% of AIDS-related deaths. Recent studies have shown that the absence sterol β-glucosidase (EGCrP2, also known as Sgl1) in significantly attenuates its virulence mouse infection model. However, mechanisms underlying this attenuation remain unclear. In study, we observed significant increase dead cells after 3 days culture SGL1 -deficient sgl1 Δ, KO) at 37°C, compared with wild-type (WT) and -reconstituted Δ:: , RE). qPCR analysis WT, KO, RE strains indicated autophagy-related genes ATG s) were downregulated KO strain. Atg8-dependent GFP translocation to vacuole was delayed strain under starvation conditions. This autophagy dysfunction identified primary cause increased cell death nitrogen conditions 37°C. EGCrP2/Sgl1 predominantly localized vacuoles deletion results accumulation not only ergosterol β-glucoside (EG), previously reported, but acylated EGs (AEGs). AEGs much more potent than EG activating C-type lectin receptor Mincle mice, rats, humans. released from via extracellular vesicles (EVs). Chemically synthesized 18:1-EG EVs derived strain, WT or strains, enhanced cytokine production murine human dendritic cells. AEG-dependent markedly reduced Mincle-deficient number lung tissue mice substantially higher on day infection. Intranasal administration sitosterol expression burden -infected mice. These findings suggest host innate immune response activation are critical reducing