The Skn7 response regulator of Cryptococcus neoformans is involved in oxidative stress signalling and augments intracellular survival in endothelium
The Skn7 response regulator of Cryptococcus neoformans is involved in oxidative stress signalling and augments intracellular survival in endothelium
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DOI：
10.1111/j.1567-1364.2006.00065.x
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发表时间：
2006-06-01
影响因子：
3.2
通讯作者：
Janbon, G
中科院分区：
文献类型：
--
作者：
Coenjaerts, FEJ;Hoepelman, AIM;Janbon, G
新型隐球菌是隐球菌性脑膜脑炎的病原体。有越来越多的证据表明，C。新生儿是一种兼性细胞内病原体，存在于巨噬细胞和内皮细胞中。在这些细胞中赋予对吞噬溶酶体杀伤抗性的分子机制是一个关键的未解决的问题。为了深入了解真菌的适应性策略，基因表达的系列分析被用来定位在吞噬细胞内环境中差异表达的基因。通过比较C.通过将从内皮细胞回收的新生儿血清型D B3501细胞与来自自由生长的隐球菌的那些细胞进行比较，我们鉴定了来自酿酒酵母的SKN7双组分应激反应调节基因的隐球菌同源物。研究C。在内皮感染实验中，对于SKN7破坏的新生动物细胞显示出对叔丁基氢过氧化物的敏感性增加（0.7mM时100%致死率，而野生型为1.0mM）和显著降低的存活率。小鼠实验表明，SKN7破坏强烈减弱隐球菌在体内的毒力。我们建议Skn7（共）调节真菌的适应性策略，允许吞噬细胞内的生存，赋予抵抗吞噬溶酶体杀死内皮细胞。
Cryptococcus neoformans is the causative agent of cryptococcal meningoencephalitis. There is accumulating evidence that C. neoformans is a facultative intracellular pathogen, residing in macrophages and endothelium. The molecular mechanism conferring resistance to phagolysosomal killing in these cells is a key unresolved issue. To gain insight into the fungal adaptive strategies, serial analysis of gene expression was used to map genes differentially expressed in an intraphagocytic environment. By comparing transcript profiles of C. neoformans serotype D B3501 cells recovered from endothelial cells with those from free-grown cryptococci, we identified the cryptococcal homologue of the SKN7 two-component stress response regulator gene from Saccharomyces cerevisiae. Studies with C. neoformans cells disrupted for SKN7 revealed an increased susceptibility to t-butyl hydroperoxide (100% lethality at 0.7 mM, vs. 1.0 mM for wild type) and significantly lower survival rates in endothelial infection experiments. Mice experiments revealed that SKN7 disruption strongly attenuates cryptococcal virulence in vivo. We propose that Skn7 (co-)regulates the fungal adaptive strategy, allowing intraphagocytic survival by conferring resistance to phagolysosomal killing in endothelial cells.