Jacobs Ella, Dragotakes Quigly, Dos Santos Samuel Rodrigues, Smith Daniel, Dziedzic Amanda, Jedlicka Anne, Smith Barbara, Wolf Julie M, Coelho Carolina, Casadevall Arturo
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Johns Hopkins School of Medicine, Baltimore, MD, USA.
bioRxiv. 2025 May 14:2025.05.14.654083. doi: 10.1101/2025.05.14.654083.
a ubiquitous environmental fungus that causes cryptococcosis, survives in diverse environments including human hosts due to metabolic flexibility. Consequently, identifying how connects diverse metabolic pathways and virulence factor expression is important for understanding fungal pathogenesis. Peroxisomes play an essential role in metabolic homeostasis and regulation of carbon and lipid metabolism. In this article, we report a link between nickel exposure, a known hypoxia-mimetic and mitochondrial respiration inhibitor in yeast, and peroxisomal β-oxidation. Loss of the last two genes involved in the peroxisomal β-oxidation pathway, (CNAG_05721) and (CNAG_00490), resulted in cell density-dependent virulence factor defects and growth inhibition attributed to a metabolic state involving large peroxisomes. We found that increasing cell density rescued virulence factor phenotypes and growth. Our results implicate mitochondrial retrograde signaling (RTG), a previously uncharacterized pathway in in cell density sensing, peroxisomal β-oxidation pathway expression, and virulence, thus highlighting a critical role for metabolism in cryptococcal virulence.
一种引起隐球菌病的普遍存在的环境真菌，由于其代谢灵活性，能在包括人类宿主在内的多种环境中生存。因此，确定其如何连接不同的代谢途径和毒力因子表达对于理解真菌发病机制很重要。过氧化物酶体在代谢稳态以及碳和脂质代谢调节中起重要作用。在本文中，我们报告了镍暴露（一种已知的酵母缺氧模拟物和线粒体呼吸抑制剂）与过氧化物酶体β-氧化之间的联系。参与过氧化物酶体β-氧化途径的最后两个基因（CNAG_05721）和（CNAG_00490）的缺失，导致细胞密度依赖性毒力因子缺陷和生长抑制，这归因于一种涉及大型过氧化物酶体的代谢状态。我们发现增加细胞密度可挽救毒力因子表型和生长。我们的结果表明线粒体逆行信号传导（RTG），这是隐球菌中一条以前未被表征的途径，在细胞密度感应、过氧化物酶体β-氧化途径表达和毒力中起作用，从而突出了代谢在隐球菌毒力中的关键作用。
