A link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans.
A link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans.
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人类真菌病原体Neoformans在感染过程中毒力与稳态反应之间的联系。
DOI：
10.1371/journal.ppat.0030022
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发表时间：
2007-02
期刊：
影响因子：
6.7
通讯作者：
Madhani HD
中科院分区：
文献类型：
--
作者：
Chun CD;Liu OW;Madhani HD
人类的真菌病原体需要分子氧进行几种基本的生化反应，但实际上对它们如何适应感染组织的相对缺氧环境一无所知。我们分离的突变体在缺氧条件下的生长缺陷，但正常的生长在常氧条件下，在新型隐球菌，真菌性脑膜炎的最常见的原因。两个调节途径被确定：一个同源的哺乳动物甾醇反应元件结合蛋白（SREBP）胆固醇生物合成的调节途径，和其他一个双组分样途径涉及真菌特异性杂合组氨酸激酶家族成员，Tco 1。我们表明，裂解的SREBP前体同源物Sre 1-这是预测释放其DNA结合域从膜-发生在缺氧反应，和Sre 1是所需的缺氧诱导的基因编码的氧依赖性酶参与麦角甾醇合成。重要的是，无论是SREBP途径或Tco 1途径的突变体显示缺陷的能力，在宿主组织中增殖，并导致感染的小鼠的疾病，连接到我们的知识缺氧适应和致病的真核需氧菌的第一次。发现SREBP途径突变体对氟康唑（一种广泛使用的抑制麦角固醇合成的抗真菌剂）的敏感性比野生型高100倍，这表明SREBP加工抑制剂可以显著增强当前疗法的效力。寄生性环境病原体适应宿主内的敌对条件而引起疾病。我们描述了两种途径的致病性真菌隐球菌的新生，都是必要的适应缺氧，并要求其毒力。一种途径使用与哺乳动物甾醇反应元件结合蛋白（SREBP）途径同源的途径来激活参与甾醇生物合成的基因以响应低氧水平，而另一种途径涉及双组分杂合组氨酸激酶蛋白Tco 1。在实验小鼠模型中，发现含有这些途径中任一种的编码组分的基因缺失的突变株的毒性较低。这项研究表明，这种致病真菌在哺乳动物宿主中经历了低氧水平，适应这些条件对于感染很重要。靶向缺氧反应的成分可以产生更有效的治疗C。新生儿感染是造成全世界大部分艾滋病毒/艾滋病相关死亡的原因。值得注意的是，我们发现SREBP样途径的突变体对广泛使用的抗真菌药物氟康唑的敏感性比野生型细胞高出一百倍。
Fungal pathogens of humans require molecular oxygen for several essential biochemical reactions, yet virtually nothing is known about how they adapt to the relatively hypoxic environment of infected tissues. We isolated mutants defective in growth under hypoxic conditions, but normal for growth in normoxic conditions, in Cryptococcus neoformans, the most common cause of fungal meningitis. Two regulatory pathways were identified: one homologous to the mammalian sterol-response element binding protein (SREBP) cholesterol biosynthesis regulatory pathway, and the other a two-component-like pathway involving a fungal-specific hybrid histidine kinase family member, Tco1. We show that cleavage of the SREBP precursor homolog Sre1—which is predicted to release its DNA-binding domain from the membrane—occurs in response to hypoxia, and that Sre1 is required for hypoxic induction of genes encoding for oxygen-dependent enzymes involved in ergosterol synthesis. Importantly, mutants in either the SREBP pathway or the Tco1 pathway display defects in their ability to proliferate in host tissues and to cause disease in infected mice, linking for the first time to our knowledge hypoxic adaptation and pathogenesis by a eukaryotic aerobe. SREBP pathway mutants were found to be a hundred times more sensitive than wild-type to fluconazole, a widely used antifungal agent that inhibits ergosterol synthesis, suggesting that inhibitors of SREBP processing could substantially enhance the potency of current therapies. Opportunistic environmental pathogens adapt to hostile conditions within the host to cause disease. We describe two pathways in the pathogenic fungus Cryptococcus neoformans that are both necessary for adaptation to hypoxia and required for its virulence. One pathway uses a pathway homologous to the mammalian sterol-response element binding protein (SREBP) pathway to activate genes involved in sterol biosynthesis in response to low oxygen levels, while the other pathway involves the two-component hybrid histidine kinase protein Tco1. Mutant strains containing deletions of genes encoding components in either of these pathways were found to be less virulent in experimental mouse models. This study suggests that this pathogenic fungus experiences low levels of oxygen in the mammalian host, and that adaptation to these conditions is important for infection. Targeting components of the hypoxia response could yield more effective treatments for C. neoformans infections, which cause a large fraction of HIV/AIDS-related deaths worldwide. Notably, we find that mutants in the SREBP-like pathway are a hundred times more sensitive than wild-type cells to the widely used antifungal drug fluconazole.
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影响因子：
5.3
作者：
Gelbart, ME;Rechsteiner, T;Tsukiyama, T
通讯作者：
Tsukiyama, T
影响因子：
64.5
作者：
Lo, HJ;Kohler, JR;Fink, GR
通讯作者：
Fink, GR
影响因子：
3.1
作者：
Hull, CM;Cox, GM;Heitman, J
通讯作者：
Heitman, J
DOI：
10.1016/s0034-5687(01)00306-1
发表时间：
2001-11-15
期刊：
RESPIRATION PHYSIOLOGY
影响因子：
--
作者：
Erecinska, M;Silver, IA
通讯作者：
Silver, IA
影响因子：
64.5
作者：
Hughes, AL;Todd, BL;Espenshade, PJ
通讯作者：
Espenshade, PJ