Small, noncoding RNAs and the evolution of Yersinia pestis virulence

小非编码 RNA 和鼠疫耶尔森氏菌毒力的进化

基本信息

批准号：
8583236
负责人：
WYNDHAM W. LATHEM
金额：
$ 21.78万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-05 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583236
关键词：
Acute Address Affect Animal Disease Models Animal Model Animals Attention Bacteria Base Pairing Bubonic Plague Cataloging Catalogs Cells Cessation of life Clinical Code DNA Sequence Data Disease Evolution Fever Gastrointestinal Diseases Gene Expression Gene Expression Regulation Genes Genetic Genetic Drift Genome Genomics Goals Human In Vitro Infection Laboratories Mammals Measures Mediating Messenger RNA MicroRNAs Microbial Biofilms Modeling Molecular Outcome Pasteurella pseudotuberculosis Physiology Plague Plasminogen Pneumonic Plague Process Proteins Public Health Regulation Regulatory Element Route Severities Soil Staging Techniques Technology Testing Time Translations Untranslated RNA Variant Virulence Virulence Factors Water Yersinia infections Yersinia pestis cytotoxicity deep sequencing design insight mRNA Stability macrophage mortality pathogen progenitor public health relevance success transcriptome sequencing transmission process

项目摘要

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.

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丢失而发生，而且还通过这些蛋白质编码基因的调节机制的变化而发生。这些改变可能导致遗传相关的细菌在表型上非常不同。造成毁灭性疾病瘟疫的鼠疫耶尔森氏菌和引起轻微自限性疾病耶尔森氏菌病的病原体假结核耶尔森氏菌就是这种现象的绝佳例子。尽管这两个物种在遗传上高度相似，并且鼠疫耶尔森氏菌被认为是假结核耶尔森氏菌最近进化的克隆，但它们的传播途径、临床疾病表现和死亡率却截然不同。目前尚不清楚这些密切相关的物种如何引起这种表型不同的疾病。近年来，小非编码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 与目标 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鼠疫耶尔森氏菌和假结核耶尔森氏菌表达的 sRNA（又名 sRNA-ome）的全局库。该分析表明，虽然大多数已鉴定的 sRNA 基因在两个物种中都是保守的，但鼠疫耶尔森氏菌基因组编码了假结核耶尔森氏菌所缺乏的 5 个 sRNA 基因。正如我们已经表明，在肺鼠疫期间，鼠疫耶尔森氏菌特异性 sRNA 中至少有一种是完全毒力所必需的，我们假设鼠疫耶尔森氏菌在从假结核耶尔森氏菌进化过程中的 sRNA 组的变化导致了其特定能力通过改变共同的和/或不同的毒力决定因素的调节来引起疾病瘟疫。我们将使用 sRNA 基因破坏结合动物感染模型来操纵鼠疫耶尔森氏菌的 sRNA 含量，以测试每种鼠疫耶尔森氏菌特异性 sRNA 如何影响动物黑死病和肺鼠疫的严重程度和结果，如果是的话，其机制这些 sRNA 有助于产生毒力。这些研究将为细菌病原体的进化提供独特的见解。转录后水平，应该广泛适用于其他密切相关但表型不同的物种。