The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen
The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen
复制标题
DOI：
10.1111/j.1365-2958.2004.04015.x
复制
发表时间：
2004-05-01
影响因子：
3.6
通讯作者：
Braus, GH
中科院分区：
文献类型：
--
作者：
Krappmann, S;Bignell, EM;Braus, GH
我们已经克隆并鉴定了烟曲霉cpcA基因编码的氨基酸生物合成的跨途径控制系统的转录激活因子。cpcA编码酿酒酵母Gcn4p的功能性直向同源物。2.2 kb转录本的编码序列之前是两个短的上游开放阅读框，较大的一个在黑曲霉中是很保守的。缺失菌株的编码序列或整个基因座被双功能显性标记物取代时，其跨途径控制响应氨基酸饥饿受损，所选择的报告基因和特定的酶活性的分析表明。在肺曲霉菌病的小鼠模型中，cpcADelta菌株显示出减弱的毒力。在基因组位点重建的菌株中，致病性恢复至野生型水平。竞争性混合感染实验还证明cpcADelta菌株在体内存活的能力低于其野生型祖细胞。我们的数据表明，特定的压力条件下，遇到的A。真菌交叉途径控制系统在肺曲霉病中起重要作用。
We have cloned and characterized the Aspergillus fumigatus cpcA gene encoding the transcriptional activator of the cross-pathway control system of amino acid biosynthesis. cpcA encodes a functional orthologue of Saccharomyces cerevisiae Gcn4p. The coding sequence of the 2.2 kb transcript is preceded by two short upstream open reading frames, the larger one being well conserved among Aspergilli. Deletion strains in which either the coding sequence or the entire locus are replaced by a bifunctional dominant marker are impaired in their cross-pathway control response upon amino acid starvation, as demonstrated by analyses of selected reporter genes and specific enzymatic activities. In a murine model of pulmonary aspergillosis, cpcADelta strains display attenuated virulence. Pathogenicity is restored to wild-type levels in strains with reconstitution of the genomic locus. Competitive mixed infection experiments additionally demonstrate that cpcADelta strains are less able to survive in vivo than their wild-type progenitor. Our data suggest that specific stress conditions are encountered by A. fumigatus within the mammalian host and that the fungal cross-pathway control system plays a significant role in pulmonary aspergillosis.