Botts Michael R, Huang Mingwei, Borchardt Regen K, Hull Christina M
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
Eukaryot Cell. 2014 Sep;13(9):1158-68. doi: 10.1128/EC.00152-14. Epub 2014 Jul 7.
Among pathogenic environmental fungi, spores are thought to be infectious particles that germinate in the host to cause disease. The meningoencephalitis-causing yeast Cryptococcus neoformans is found ubiquitously in the environment and sporulates in response to nutrient limitation. While the yeast form has been studied extensively, relatively little is known about spore biogenesis, and spore germination has never been evaluated at the molecular level. Using genome transcript analysis of spores and molecular genetic approaches, we discovered that trehalose homeostasis plays a key role in regulating sporulation of C. neoformans, is required for full spore viability, and influences virulence. Specifically, we found that genes involved in trehalose metabolism, including a previously uncharacterized secreted trehalase (NTH2), are highly overrepresented in dormant spores. Deletion of the two predicted trehalases in the C. neoformans genome, NTH1 and NTH2, resulted in severe defects in spore production, a decrease in spore germination, and an increase in the production of alternative developmental structures. This shift in cell types suggests that trehalose levels modulate cell fate decisions during sexual development. We also discovered that deletion of the NTH2 trehalase results in hypervirulence in a murine model of infection. Taken together, these data show that the metabolic adaptations that allow this fungus to proliferate ubiquitously in the environment play unexpected roles in virulence in the mammalian host and highlight the complex interplay among the processes of metabolism, development, and pathogenesis.
在致病性环境真菌中，孢子被认为是感染性颗粒，可在宿主体内萌发并引发疾病。导致脑膜脑炎的新型隐球菌酵母在环境中普遍存在，并在营养受限的情况下形成孢子。虽然对酵母形态已进行了广泛研究，但对孢子生物发生的了解相对较少，且从未在分子水平上评估过孢子萌发。通过对孢子进行基因组转录分析和分子遗传学方法，我们发现海藻糖稳态在调节新型隐球菌的孢子形成中起关键作用，是孢子完全存活所必需的，并影响毒力。具体而言，我们发现参与海藻糖代谢的基因，包括一种先前未被表征的分泌型海藻糖酶（NTH2），在休眠孢子中高度富集。删除新型隐球菌基因组中两个预测的海藻糖酶NTH1和NTH2，导致孢子产生严重缺陷、孢子萌发减少以及替代发育结构的产生增加。细胞类型的这种转变表明海藻糖水平在有性发育过程中调节细胞命运决定。我们还发现，删除NTH2海藻糖酶会导致小鼠感染模型中的毒力增强。综上所述，这些数据表明，使这种真菌能够在环境中广泛增殖的代谢适应在哺乳动物宿主的毒力中发挥了意想不到的作用，并突出了代谢、发育和发病机制过程之间的复杂相互作用。
