Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice
Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice
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DOI：
10.1172/jci45169
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Musser, James M.
中科院分区：
文献类型：
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作者：
Carroll, Ronan K.;Shelburne, Samuel A., III;Musser, James M.
感染同一种细菌的不同菌株往往会导致非常不同的临床结果。尽管进行了广泛的调查，但微生物菌株特异性毒力的遗传基础仍然知之甚少。最近的全基因组测序显示，SNPs是同一物种细菌的不同菌株中最普遍的遗传多样性形式。在侵袭性血清型M3 A组链球菌(GAS)菌株中，编码蛋白酶B调节基因(RopB)的SNPs频率最高。在这里，我们已经确定了ropB基因的多态性改变了RopB的功能，并调节了GAS宿主与病原体的相互作用。对171株侵袭性M3型GAS菌株的ropB基因进行测序，鉴定出19个不同的ropB等位基因。在产生不同RopB变异体的菌株中，ropB基因的失活对GAS全局基因表达的影响显著不同。此外，RopB中只有一个氨基酸差异的等位基因GAS菌株的产生证实，变异蛋白影响了编码链球菌蛋白酶B的基因的转录水平，这是RopB调节的主要毒力因子。在小鼠感染模型中比较亲本株、RopB灭活株和RopB等位基因株表明，ropB基因多态影响GAS毒力和疾病表现。这些数据详细说明了一种范式，在这种范式中，对临床细菌分离株群体的无偏倚全基因组序列分析为常见人类感染的发病机制创造了新的生产性研究途径。
Infection with different strains of the same species of bacteria often results in vastly different clinical outcomes. Despite extensive investigation, the genetic basis of microbial strain-specific virulence remains poorly understood. Recent whole-genome sequencing has revealed that SNPs are the most prevalent form of genetic diversity among different strains of the same species of bacteria. For invasive serotype M3 group A streptococci (GAS) strains, the gene encoding regulator of proteinase B (RopB) has the highest frequency of SNPs. Here, we have determined that ropB polymorphisms alter RopB function and modulate GAS host-pathogen interactions. Sequencing of ropB in 171 invasive serotype M3 GAS strains identified 19 distinct ropB alleles. Inactivation of the ropB gene in strains producing distinct RopB variants had dramatically divergent effects on GAS global gene expression. Additionally, generation of isoallelic GAS strains differing only by a single amino acid in RopB confirmed that variant proteins affected transcript levels of the gene encoding streptococcal proteinase B, a major RopB-regulated virulence factor. Comparison of parental, RopB-inactivated, and RopB isoallelic strains in mouse infection models demonstrated that ropB polymorphisms influence GAS virulence and disease manifestations. These data detail a paradigm in which unbiased, whole-genome sequence analysis of populations of clinical bacterial isolates creates new avenues of productive investigation into the pathogenesis of common human infections.