Regulatory rewiring confers serotype-specific hyper-virulence in the human pathogen group A Streptococcus.
Regulatory rewiring confers serotype-specific hyper-virulence in the human pathogen group A Streptococcus.
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DOI：
10.1111/mmi.13136
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发表时间：
2015-10
影响因子：
3.6
通讯作者：
Sumby P
中科院分区：
文献类型：
--
作者：
Miller EW;Danger JL;Ramalinga AB;Horstmann N;Shelburne SA;Sumby P
表型异质性通常在特定病原体的分离株之间观察到。流行病学分析已经确定，某些血清型的A群链球菌（GAS）与特定疾病表现非随机相关。在这里，我们提出证据表明，血清型M3 GAS分离物与严重侵袭性感染相关的一个促成因素是孤儿激酶RocA的零突变等位基因的存在。通过RNAseq分析，我们发现M3分离株中存在的天然rocA突变导致十多种免疫调节毒力因子的表达增强，增强了溶血和NAD+水解等表型。因此，M3 GAS分离物在人类吞噬杀死中存活的水平比rocA补充衍生物高13倍，并且在小鼠菌血症感染模型中具有更强的毒性。最后，我们发现RocA通过CovR/S双组分系统发挥作用，因为在功能性RocA存在时，磷酸化的CovR水平会增加，而在CovR或covS突变后，RocA没有调节活性。我们的数据与RocA与CovR/S双组分系统的界面一致，并且M3 GAS中缺乏这种活性增强了该血清型分离株引起的侵袭性感染的严重程度。
Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A Streptococcus (GAS) are non-randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA. Through use of RNAseq analysis, we identified that the natural rocA mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD+ hydrolysis. Consequently, an M3 GAS isolate survived human phagocytic killing at a level 13-fold higher than a rocA complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA functions through the CovR/S two-component system as levels of phosphorylated CovR increase in the presence of functional RocA, and RocA has no regulatory activity following covR or covS mutation. Our data are consistent with RocA interfacing with the CovR/S two-component system, and that the absence of this activity in M3 GAS potentiates the severity of invasive infections caused by isolates of this serotype.