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首页> 外文期刊>Infection and immunity >Transcription of the Streptococcus pyogenes Hyaluronic Acid Capsule Biosynthesis Operon Is Regulated by Previously Unknown Upstream Elements
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Transcription of the Streptococcus pyogenes Hyaluronic Acid Capsule Biosynthesis Operon Is Regulated by Previously Unknown Upstream Elements

机译：化脓性链球菌透明质酸胶囊生物合成操纵子的转录受先前未知的上游因素调控。

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The important human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]) produces a hyaluronic acid (HA) capsule that plays critical roles in immune evasion. Previous studies showed that the hasABC operon encoding the capsule biosynthesis enzymes is under the control of a single promoter, P1, which is negatively regulated by the two-component regulatory system CovR/S. In this work, we characterize the sequence upstream of P1 and identify a novel regulatory region controlling transcription of the capsule biosynthesis operon in the M1 serotype strain MGAS2221. This region consists of a promoter, P2, which initiates transcription of a novel small RNA, HasS, an intrinsic transcriptional terminator that inefficiently terminates HasS, permitting read-through transcription of hasABC, and a putative promoter which lies upstream of P2. Electrophoretic mobility shift assays, quantitative reverse transcription-PCR, and transcriptional reporter data identified CovR as a negative regulator of P2. We found that the P1 and P2 promoters are completely repressed by CovR, and capsule expression is regulated by the putative promoter upstream of P2. Deletion of hasS or of the terminator eliminates CovR-binding sequences, relieving repression and increasing read-through, hasA transcription, and capsule production. Sequence analysis of 44 GAS genomes revealed a high level of polymorphism in the HasS sequence region. Most of the HasS variations were located in the terminator sequences, suggesting that this region is under strong selective pressure. We discovered that the terminator deletion mutant is highly resistant to neutrophil-mediated killing and is significantly more virulent in a mouse model of GAS invasive disease than the wild-type strain. Together, these results are consistent with the naturally occurring mutations in this region modulating GAS virulence.
机译：重要的人类病原体化脓性链球菌（A群链球菌[GAS]）产生透明质酸（HA）胶囊，在免疫逃逸中起关键作用。先前的研究表明，编码胶囊生物合成酶的hasABC操纵子受单个启动子P1的控制，该启动子受两组分调节系统CovR / S负调节。在这项工作中，我们表征了P1上游的序列，并确定了一个新的调控区域，该区域控制M1血清型菌株MGAS2221中的胶囊生物合成操纵子的转录。该区域由启动子P2和推定的启动子组成，启动子P2启动新的小RNA的转录，HasS是无效地终止HasS的固有转录终止子，允许hasABC的通读转录，而推定的启动子位于P2的上游。电泳迁移率变动分析，定量逆转录PCR和转录报告数据确定CovR为P2的负调节剂。我们发现P1和P2启动子完全被CovR抑制，并且胶囊表达受P2上游假定的启动子调控。 hasS或终止子的缺失消除了CovR结合序列，减轻了抑制并增加了通读，hasA转录和胶囊的产生。对44个GAS基因组的序列分析显示，HasS序列区域具有高度的多态性。大多数HasS变异位于终止子序列中，表明该区域处于强大的选择压力下。我们发现终止子缺失突变体对中性粒细胞介导的杀伤具有高度抗性，并且在GAS侵袭性疾病的小鼠模型中比野生型菌株更具毒性。总之，这些结果与该区域中调节GAS毒力的自然突变相符。

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