Candida albicans uses multiple mechanisms to acquire the essential metabolite inositol during infection
Candida albicans uses multiple mechanisms to acquire the essential metabolite inositol during infection
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DOI：
10.1128/iai.01514-07
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发表时间：
2008-06-01
影响因子：
3.1
通讯作者：
Reynolds, Todd B.
中科院分区：
文献类型：
--
作者：
Chen, Ying-Lien;Kauffman, Sarah;Reynolds, Todd B.
白色念珠菌是免疫功能低下患者危及生命的全身血流感染的重要原因。为了引起感染，白色念珠菌必须能够合成必需的代谢物肌醇或从宿主获取它。基于白色念珠菌与酿酒酵母的相似性，预测白色念珠菌可能从头产生肌醇、从环境中输入肌醇，或两者兼而有之。白色念珠菌肌醇合成基因INO1 (orf19.7585)和肌醇转运蛋白基因ITR1 (orf19.3526)均被破坏。 ino1 Delta/ino1 Delta 突变体是肌醇营养缺陷型，并且 itr1 Delta/itr1 Delta 突变体无法从培养基中导入肌醇。这些突变体中的每一个在全身感染的小鼠模型中都具有完全的毒力。不可能产生 ino1 Delta/ino1 Delta itr1 Delta/itr1 Delta 双突变体，这表明在缺乏这两个基因的情况下，白色念珠菌无法获得肌醇并且无法存活。通过用由可抑制的 MET3 启动子驱动的 ITRI 条件表达等位基因替换 ino1 Delta/ino1 Delta itr1 Delta/ITR1 菌株中剩余的 ITR1 野生型等位基因，创建了条件双突变体。发现所得的 ino1 Delta/ino1 Delta itr1 Delta/P-MET3::ITR1 菌株在含有蛋氨酸和半胱氨酸（抑制启动子）的培养基中无法存活，并且在系统性念珠菌病小鼠模型中无毒力。这些结果表明，白色念珠菌在宿主体内有两种同样有效的获取肌醇的机制。它可以通过 Ino1p 从头生成肌醇，也可以通过 Itr1p 从宿主导入。
Candida albicans is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections, C. albicans must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of C. albicans to Saccharomyces cerevisiae, it was predicted that C. albicans may generate inositol de novo, import it from the environment, or both. The C. albicans inositol synthesis gene INO1 (orf19.7585) and inositol transporter gene ITR1 (orf19.3526) were each disrupted. The ino1 Delta/ino1 Delta mutant was an inositol auxotroph, and the itr1 Delta/itr1 Delta mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an ino1 Delta/ino1 Delta itr1 Delta/itr1 Delta double mutant, suggesting that in the absence of these two genes, C. albicans could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of ITR1 in an ino1 Delta/ino1 Delta itr1 Delta/ITR1 strain with a conditionally expressed allele of ITRI driven by the repressible MET3 promoter. The resulting ino1 Delta/ino1 Delta itr1 Delta/P-MET3::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which C. albicans has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.