Species-Wide Phylogenomics of the Staphylococcus aureus Agr Operon Revealed Convergent Evolution of Frameshift Mutations.
Species-Wide Phylogenomics of the Staphylococcus aureus Agr Operon Revealed Convergent Evolution of Frameshift Mutations.
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金黄色葡萄球菌AGR操纵子的全物种系统基因组学揭示了移码突变的趋同进化。
DOI：
10.1128/spectrum.01334-21
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发表时间：
2022-02-23
影响因子：
3.7
通讯作者：
Read TD
中科院分区：
文献类型：
--
作者：
Raghuram V;Alexander AM;Loo HQ;Petit RA 3rd;Goldberg JB;Read TD
金黄色葡萄球菌是一种主要的医院内病原体，可引起多种危及生命的疾病，如肺炎和菌血症。金黄色葡萄球菌通过感知和整合对环境信号的反应来调节其毒力因子的表达。群体感应系统是金黄色葡萄球菌毒力表型的主要调控因子。有四个agr特异性组，每个组都有一个由agrD基因编码的不同的自身诱导肽序列。虽然agr对许多毒素的表达是关键的，但矛盾的是，金黄色葡萄球菌菌株往往由于四基因agr操纵子功能丧失突变而具有不起作用的agr活性。为了了解金黄色葡萄球菌AGR可变性的模式，我们进行了全物种的基因组研究。我们开发了一个软件工具(ANGVATE；https://github.com/VishnuRaghuram94/AgrVATE))，用于分型和检测agr操纵子的移码突变。在对40,000多个金黄色葡萄球菌基因组的分析中，我们显示了agr类型与金黄色葡萄球菌克隆复合体之间的密切联系。我们还发现agrBDC等位基因(分别编码多肽酶、自我诱导多肽本身和多肽传感器)之间存在很强的联系，但没有发现agrBDC等位基因(编码反应调节因子)之间存在很强的联系。超过5%的基因组被发现在agr操纵子上有移码突变。虽然52%的移码在整个物种中只发生一次，但我们观察到反复发生的突变在不同的克隆谱系中收敛地进化，没有证据表明长期的系统发育传播，这表明带有AGR移码的菌株在进化上是短暂的。总体而言，对agr操纵子的基因组分析表明，通过多个过程进行进化，其功能后果尚未完全理解。重要性金黄色葡萄球菌是一种全球普遍存在的病原体，它会产生过量的有毒分子，会损害宿主免疫细胞。这些毒素的产生主要由一个主动的群体感应系统控制，该系统感知细菌细胞密度并对其做出反应。然而，有许多关于金黄色葡萄球菌菌株的基因改变导致agr活性受损的报道，这些菌株通常在慢性血流感染期间被发现，并可能与疾病严重程度的增加有关。我们开发了一款名为AGVATE的开源软件，用于对agr系统进行分型并识别突变。我们使用AGVATE对金黄色葡萄球菌进行了全物种的基因组调查，发现公共数据库中超过5%的菌株具有非功能的AGR系统。我们还对AGR系统中这些基因突变的进化提供了新的见解。总体而言，这项研究有助于我们理解金黄色葡萄球菌毒力调节的一种常见但相对较少的研究手段。
Staphylococcus aureus is a prominent nosocomial pathogen that causes several life-threatening diseases, such as pneumonia and bacteremia. S. aureus modulates the expression of its arsenal of virulence factors through sensing and integrating responses to environmental signals. The agr (accessory gene regulator) quorum sensing (QS) system is a major regulator of virulence phenotypes in S. aureus. There are four agr specificity groups each with a different autoinducer peptide sequence encoded by the agrD gene. Although agr is critical for the expression of many toxins, paradoxically, S. aureus strains often have nonfunctional agr activity due to loss-of-function mutations in the four-gene agr operon. To understand patterns in agr variability across S. aureus, we undertook a species-wide genomic investigation. We developed a software tool (AgrVATE; https://github.com/VishnuRaghuram94/AgrVATE) for typing and detecting frameshift mutations in the agr operon. In an analysis of over 40,000 S. aureus genomes, we showed a close association between agr type and S. aureus clonal complex. We also found a strong linkage between agrBDC alleles (encoding the peptidase, autoinducing peptide itself, and peptide sensor, respectively) but not agrA (encoding the response regulator). More than 5% of the genomes were found to have frameshift mutations in the agr operon. While 52% of these frameshifts occurred only once in the entire species, we observed cases where the recurring mutations evolved convergently across different clonal lineages with no evidence of long-term phylogenetic transmission, suggesting that strains with agr frameshifts were evolutionarily short-lived. Overall, genomic analysis of agr operon suggests evolution through multiple processes with functional consequences that are not fully understood. IMPORTANCE Staphylococcus aureus is a globally pervasive pathogen that produces a plethora of toxic molecules that can harm host immune cells. Production of these toxins is mainly controlled by an active agr quorum-sensing system, which senses and responds to bacterial cell density. However, there are many reports of S. aureus strains with genetic changes leading to impaired agr activity that are often found during chronic bloodstream infections and may be associated with increased disease severity. We developed an open-source software called AgrVATE to type agr systems and identify mutations. We used AgrVATE for a species-wide genomic survey of S. aureus, finding that more than 5% of strains in the public database had nonfunctional agr systems. We also provided new insights into the evolution of these genetic mutations in the agr system. Overall, this study contributes to our understanding of a common but relatively understudied means of virulence regulation in S. aureus.
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