Centro de Biotecnologia, UFRGS, Porto Alegre, RS, Brazil.
Laboratório Nacional de Computação Científica (LNCC), Petrópolis, RJ, Brazil.
Cell Microbiol. 2018 Feb;20(2). doi: 10.1111/cmi.12803. Epub 2017 Nov 23.
Cryptococcus neoformans is a basidiomycetous yeast and the cause of cryptococcosis in immunocompromised individuals. The most severe form of the disease is meningoencephalitis, which is one of the leading causes of death in HIV/AIDS patients. In order to access the central nervous system, C. neoformans relies on the activity of certain virulence factors such as urease, which allows transmigration through the blood-brain barrier. In this study, we demonstrate that the calcium transporter Pmc1 enables C. neoformans to penetrate the central nervous system, because the pmc1 null mutant failed to infect and to survive within the brain parenchyma in a murine systemic infection model. To investigate potential alterations in transmigration pathways in these mutants, global expression profiling of the pmc1 mutant strain was undertaken, and genes associated with urease, the Ca -calcineurin pathway, and capsule assembly were identified as being differentially expressed. Also, a decrease in urease activity was observed in the calcium transporter null mutants. Finally, we demonstrate that the transcription factor Crz1 regulates urease activity and that the Ca -calcineurin signalling pathway positively controls the transcription of calcium transporter genes and factors related to transmigration.
新生隐球菌是一种担子菌酵母，也是免疫功能低下个体中 cryptococcosis 的病因。该病最严重的形式是脑膜脑炎，是 HIV/AIDS 患者死亡的主要原因之一。为了进入中枢神经系统，新生隐球菌依赖于某些毒力因子的活性，如脲酶，这使其能够穿过血脑屏障。在这项研究中，我们证明了钙转运蛋白 Pmc1 使新生隐球菌能够穿透中枢神经系统，因为 pmc1 缺失突变体在小鼠系统性感染模型中未能感染和在脑实质中存活。为了研究这些突变体中穿细胞迁移途径的潜在变化，对 pmc1 突变菌株的全基因表达谱进行了研究，确定了与脲酶、Ca-钙调神经磷酸酶途径和荚膜组装相关的基因表达存在差异。此外，还观察到钙转运蛋白缺失突变体中的脲酶活性降低。最后，我们证明转录因子 Crz1 调节脲酶活性，而 Ca-钙调神经磷酸酶信号通路正向控制钙转运蛋白基因和与穿细胞迁移相关的因子的转录。
