Small, noncoding RNAs and the evolution of Yersinia pestis virulence

描述（由申请人提供）：细菌病原体的进化不仅通过蛋白质编码基因的获得或丧失发生，而且还通过调节这些蛋白质编码基因的机制的变化发生。这些改变可能导致表型上非常不同的遗传相关细菌。造成毁灭性疾病鼠疫的鼠疫耶尔森氏菌和引起轻度自限性疾病耶尔森氏菌病的假结核耶尔森氏菌是这种现象的很好例子。虽然这两个物种在遗传上高度相似，但Y.鼠疫菌被认为是最近进化的Y.假结核病的传播途径、临床疾病表现和死亡率各不相同。目前还不清楚这些密切相关的物种如何导致这种表型不同的疾病。近年来，小的非编码RNA（sRNA）在转录后水平对基因表达的调控引起了人们的广泛关注。sRNA与靶mRNA碱基配对以改变翻译速率，从而影响蛋白质丰度。通过使用深度测序技术，我的实验室最近确定了由Y.鼠疫菌和Y.假结核这项分析表明，虽然大多数sRNA基因在两个物种中是保守的，但Y。鼠疫菌基因组编码5个sRNA基因，在鼠疫耶尔森氏菌中缺失。假结核正如我们已经证明的，这些Y.鼠疫特异性sRNAs是肺鼠疫完全毒力所必需的，我们推测，Y.鼠疫菌是从Y.假结核病通过改变共同和/或不同毒力决定因子的调节而促成其引起疾病鼠疫的特定能力。我们将使用sRNA基因破坏结合感染动物模型来操纵Y的sRNA含量。以测试每个Y.鼠疫特异性sRNA可能会影响动物腺鼠疫和肺鼠疫的严重程度和结果，如果是这样，这些sRNA有助于毒力的机制。这些研究将提供一个独特的洞察细菌病原体的演变， 转录后水平，并应广泛适用于其他密切相关，但表型不同的物种。

DESCRIPTION (provided by applicant): The evolution of bacterial pathogens not only occurs through the gain or loss of protein-coding genes but also through changes in the mechanisms by which those protein-coding genes are regulated. These alterations may result in genetically related bacteria that are phenotypically quite distinct. Yersinia pestis, responsible for the devastating disease plague, and Yersinia pseudotuberculosis, the causative agent of the mild, self-limiting disease Yersiniosis, are excellent examples of this phenomenon. Although these two species are highly genetically similar and Y. pestis is considered to be a recently evolved clone of Y. pseudotuberculosis, the routes of transmission, clinical disease manifestations, and mortality rates caused by each are dramatically different. It is still unclear as to how these closely related species cause such phenotypically distinct diseases. In recent years, the regulation of gene expression at the post-transcriptional level by small, noncoding RNAs (sRNAs) has gained considerable attention. sRNAs base-pair with target mRNAs to alter translation rates and therefore affect protein abundance. By using deep sequencing technology, my laboratory recently determined the global repertoire of sRNAs (aka the sRNA-ome) expressed by both Y. pestis and Y. pseudotuberculosis. This analysis revealed that, while the majority of sRNA genes identified are conserved in both species, the Y. pestis genome encodes 5 sRNA genes that are absent from Y. pseudotuberculosis. As we have shown that at least one of these Y. pestis-specific sRNAs is required for full virulence during pneumonic plague, we hypothesize that changes in the sRNA-ome of Y. pestis during its evolution from Y. pseudotuberculosis contributed to its specific ability to cause the disease plague by changing the regulation of shared and/or distinct virulence determinants. We will use sRNA gene disruption combined with animal models of infection to manipulate the sRNA content of Y. pestis to test how each Y. pestis-specific sRNA may affect the severity and outcome of bubonic and pneumonic plague in animals and if so, the mechanisms by which these sRNAs contribute to virulence. These studies will provide a unique insight into the evolution of bacterial pathogens at the post-transcriptional level and should be broadly applicable to other closely related but phenotypically distinct species.