Beres Stephen B, Richter Ellen W, Nagiec Michal J, Sumby Paul, Porcella Stephen F, DeLeo Frank R, Musser James M
Center for Molecular and Translational Human Infectious Diseases Research, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7059-64. doi: 10.1073/pnas.0510279103. Epub 2006 Apr 24.
In recent years we have studied the relationship between strain genotypes and patient phenotypes in group A Streptococcus (GAS), a model human bacterial pathogen that causes extensive morbidity and mortality worldwide. We have concentrated our efforts on serotype M3 organisms because these strains are common causes of pharyngeal and invasive infections, produce unusually severe invasive infections, and can exhibit epidemic behavior. Our studies have been hindered by the lack of genome-scale phylogenies of multiple GAS strains and whole-genome sequences of multiple serotype M3 strains recovered from individuals with defined clinical phenotypes. To remove some of these impediments, we sequenced to closure the genome of four additional GAS strains and conducted comparative genomic resequencing of 12 contemporary serotype M3 strains representing distinct genotypes and phenotypes. Serotype M3 strains are a single phylogenetic lineage. Strains from asymptomatic throat carriers were significantly less virulent for mice than sterile-site isolates and evolved to a less virulent phenotype by multiple genetic pathways. Strain persistence or extinction between epidemics was strongly associated with presence or absence, respectively, of the prophage encoding streptococcal pyrogenic exotoxin A. A serotype M3 clone significantly underrepresented among necrotizing fasciitis cases has a unique frameshift mutation that truncates MtsR, a transcriptional regulator controlling expression of genes encoding iron-acquisition proteins. Expression microarray analysis of this clone confirmed significant alteration in expression of genes encoding iron metabolism proteins. Our analysis provided unprecedented detail about the molecular anatomy of bacterial strain genotype-patient phenotype relationships.
近年来，我们研究了A群链球菌（GAS）中菌株基因型与患者表型之间的关系。GAS是一种典型的人类细菌病原体，在全球范围内导致大量发病和死亡。我们将研究重点集中在M3血清型菌株上，因为这些菌株是咽部和侵袭性感染的常见病因，会引发异常严重的侵袭性感染，并且可能呈现流行态势。由于缺乏多种GAS菌株的全基因组系统发育树以及从具有明确临床表型的个体中分离出的多种M3血清型菌株的全基因组序列，我们的研究受到了阻碍。为了消除这些障碍，我们对另外4株GAS菌株进行了全基因组测序，并对代表不同基因型和表型的12株当代M3血清型菌株进行了比较基因组重测序。M3血清型菌株属于单一系统发育谱系。来自无症状咽部携带者的菌株对小鼠的毒性明显低于无菌部位分离株，并且通过多种遗传途径演变为毒性较低的表型。菌株在流行期间的持续存在或灭绝分别与编码链球菌致热外毒素A的前噬菌体的存在或缺失密切相关。在坏死性筋膜炎病例中显著代表性不足的一个M3血清型克隆有一个独特的移码突变，该突变截断了MtsR，MtsR是一种转录调节因子，控制着编码铁获取蛋白的基因的表达。对该克隆进行的表达微阵列分析证实了编码铁代谢蛋白的基因表达有显著改变。我们的分析提供了关于细菌菌株基因型与患者表型关系的分子解剖学前所未有的详细信息。
