Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis
Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis
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新型隐球菌铜稳态机制在肺部感染和脑膜脑炎过程中的相互作用
DOI：
10.1038/ncomms6550
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发表时间：
2014-11-01
影响因子：
16.6
通讯作者：
Ding, Chen
中科院分区：
文献类型：
--
作者：
Sun, Tian-Shu;Ju, Xiao;Ding, Chen
铜的体内平衡对于新型隐球菌的毒力很重要，新型隐球菌可导致人类致命的脑膜脑炎。隐球菌细胞在肺中遇到高铜水平，在那里感染开始，在大脑中遇到低铜水平。在这里，我们证明了两个隐球菌铜转运蛋白，Ctr1和Ctr4，差异影响真菌的生存在肺部感染和脑膜脑炎的发病。蛋白质Ctr1在感染肺中发现的高铜条件下迅速降解，其损失对小鼠中的真菌毒力没有影响。相比之下，删除CTR 4导致高毒力表型。过度表达Ctr1或Ctr4导致肺中真菌负荷的显著降低。然而，在脑膜脑炎的发病过程中，铜转运蛋白的表达被诱导，并且对隐球菌的毒力至关重要。我们的工作表明，真菌细胞在铜解毒和获得之间切换，以解决宿主中不同的铜胁迫。
Copper homeostasis is important for virulence of the fungus Cryptococcus neoformans, which can cause lethal meningoencephalitis in humans. Cryptococcus cells encounter high copper levels in the lung, where infection is initiated, and low copper levels in the brain. Here we demonstrate that two Cryptococcus copper transporters, Ctr1 and Ctr4, differentially influence fungal survival during pulmonary infection and the onset of meningoencephalitis. Protein Ctr1 is rapidly degraded under the high-copper conditions found in infected lungs, and its loss has no effect in fungal virulence in mice. By contrast, deleting CTR4 results in a hypervirulent phenotype. Overexpressing either Ctr1 or Ctr4 leads to profound reductions in fungal burden in the lung. However, during the onset of meningoencephalitis, expression of the copper transporters is induced and is critical for Cryptococcus virulence. Our work demonstrates that the fungal cells switch between copper detoxification and acquisition to address different copper stresses in the host.