A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.
A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.
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A 组链球菌的多基因调节因子中天然存在的单一氨基酸替代显着增加了毒力。
DOI：
10.1016/j.ajpath.2014.10.018
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Olsen,RandallJ
中科院分区：
文献类型：
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作者：
Sanson,Misu;O'Neill,BrianE;Kachroo,Priyanka;Anderson,JeffR;Flores,AnthonyR;Valson,Chandni;Cantu,ConcepcionC;Makthal,Nishanth;Karmonik,Christof;Fittipaldi,Nahuel;Kumaraswami,Muthiah;Musser,JamesM;Olsen,RandallJ
单核苷酸多态性（SNPs）是一个物种内遗传变异的最常见来源;然而，很少有研究表明天然存在的SNPs可能会增加菌株的毒力。我们最近使用A组链球菌作为模式病原体来研究细菌菌株基因型与患者疾病表型的关系。全基因组测序约800血清型M59 A组链球菌菌株，在北美严重侵袭性感染爆发期间恢复，确定了编码A组链球菌（mga）多基因调节因子的基因中不成比例的SNP数量。在这里，我们报告的研究结果，旨在测试的假设，最常见的SNP，编码精氨酸的组氨酸在密码子201 Mga（H201 R）的替代，显着增加毒力。全转录组分析显示，H201 R替换显著增加了mga和54个其他基因的表达，包括许多已证实的毒力因子。与野生型菌株相比，H201 R同基因突变株在小鼠中引起显著更大的皮肤病变。连续定量细菌培养和非侵入性磁共振成像也表明，同基因H201 R菌株在非人灵长类动物联合感染模型中的毒性明显更强。这些发现表明，Mga中的H201 R替换增加了M59 A组链球菌的毒力，并为细菌中天然存在的SNP如何影响人类疾病表型提供了新的见解。
Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype–patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga). Herein, we report results of studies designed to test the hypothesis that the most commonly occurring SNP, encoding a replacement of arginine for histidine at codon 201 of Mga (H201R), significantly increases virulence. Whole transcriptome analysis revealed that the H201R replacement significantly increased expression ofmgaand 54 other genes, including many proven virulence factors. Compared to the wild-type strain, a H201R isogenic mutant strain caused significantly larger skin lesions in mice. Serial quantitative bacterial culture and noninvasive magnetic resonance imaging also demonstrated that the isogenic H201R strain was significantly more virulent in a nonhuman primate model of joint infection. These findings show that the H201R replacement in Mga increases the virulence of M59 group A Streptococcus and provide new insight to how a naturally occurring SNP in bacteria contributes to human disease phenotypes.