Section of Infectious Diseases, Department of Pediatrics, Texas Children's Hospital and Baylor College of MedicineHouston, Texas, USA.
Infect Immun. 2013 Nov;81(11):4128-38. doi: 10.1128/IAI.00405-13. Epub 2013 Aug 26.
Humans commonly carry pathogenic bacteria asymptomatically, but the molecular factors underlying microbial asymptomatic carriage are poorly understood. We previously reported that two epidemiologically unassociated serotype M3 group A Streptococcus (GAS) carrier strains had an identical 12-bp deletion in the promoter of the gene encoding Mga, a global positive gene regulator. Herein, we report on studies designed to test the hypothesis that the identified 12-bp deletion in the mga promoter alters GAS virulence, thereby potentially contributing to the asymptomatic carrier phenotype. Using allelic exchange, we introduced the variant promoter into a serotype M3 invasive strain and the wild-type promoter into an asymptomatic carrier strain. Compared to strains with the wild-type mga promoter, we discovered that strains containing the promoter with the 12-bp deletion produced significantly fewer mga and Mga-regulated gene transcripts. Consistent with decreased mga transcripts, strains containing the variant mga promoter were also significantly less virulent in in vivo and ex vivo models of GAS disease. Further, we provide evidence that the pleiotropic regulator protein CodY binds to the mga promoter and that the 12-bp deletion in the mga promoter reduces CodY-mediated mga transcription. We conclude that the naturally occurring 12-bp deletion in the mga promoter significantly alters the pathogen-host interaction of these asymptomatic carrier strains. Our findings provide new insight into the molecular basis of the carrier state of an important human pathogen.
人类通常无症状携带病原菌，但微生物无症状携带的分子因素仍知之甚少。我们之前曾报道过，两株在流行病学上无关联的 M3 型 A 组链球菌（GAS）携带者菌株在编码 Mga 的基因启动子中存在相同的 12 个碱基对缺失，Mga 是一种全局阳性基因调节剂。在此，我们报告了旨在检验以下假设的研究：Mga 启动子中鉴定出的 12 个碱基对缺失改变 GAS 毒力，从而可能导致无症状携带表型。我们通过等位基因交换将变体启动子引入 M3 型侵袭性菌株中，并将野生型启动子引入无症状携带菌株中。与携带野生型 mga 启动子的菌株相比，我们发现含有 12 个碱基对缺失的启动子的菌株产生的 mga 和 Mga 调控基因转录本显著减少。与 mga 转录本减少一致，含有变体 mga 启动子的菌株在 GAS 疾病的体内和体外模型中也明显毒力降低。此外，我们提供了证据表明多效调控蛋白 CodY 结合到 mga 启动子上，并且 mga 启动子中的 12 个碱基对缺失减少了 CodY 介导的 mga 转录。我们得出结论，mga 启动子中自然发生的 12 个碱基对缺失显著改变了这些无症状携带菌株的病原体-宿主相互作用。我们的发现为重要人类病原体的携带状态的分子基础提供了新的见解。
