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：
8730080
负责人：
WYNDHAM W. LATHEM
金额：
$ 19.31万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730080
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

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

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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是通过蛋白质编码基因的增益或丢失而发生的，而且还通过调节这些蛋白质编码基因的机制的变化而发生。这些改变可能会导致在表型上完全不同的遗传相关细菌。负责毁灭性疾病瘟疫的耶尔森氏菌，而轻度，自限性疾病yersiniosis的病原体耶尔森氏菌是这种现象的极好例子。尽管这两种物种在遗传上高度相似，而鼠疫被认为是Y. pseudotuberculcolisos的最近进化的克隆，传播的途径，临床疾病表现和由每种引起的死亡率大不相同。对于这些密切相关的物种如何引起这种表型不同的疾病，仍然不清楚。近年来，小型非编码RNA（SRNA）在转录后水平上调节基因表达已引起了人们的关注。具有目标mRNA的SRNA碱基对改变了翻译率，因此影响蛋白质丰度。通过使用深层测序技术，我的实验室最近确定了Y. Pestis和Y. pseudotuberculculosis表达的SRNA（又名SRNA-OME）的全球曲目。该分析表明，尽管鉴定出的大多数SRNA基因在这两种物种中都是保守的，但Pestis基因组编码了Y. pseudotuberculculosis中没有的5个SRNA基因。正如我们已经表明的那样，在肺炎瘟疫期间完全毒力需要这些pestis特异性的srNA中的至少一个，我们假设鼠疫菌在Y. pseudotuberculcis中的演变中的变化Y. pestis的srna-Ome变化有助于导致其特定能力通过更改疾病的疾病来通过共享和或不同的疾病来确定疾病的特定能力。我们将使用SRNA基因破坏与感染的动物模型来操纵Pestis的SRNA含量，以测试每个Y. Pestis特异性的SRNA如何影响动物中的泡泡声和肺炎的严重程度和结果，如果是这样，这些SRNA对这些SRNA有助于毒力的机制。这些研究将为细菌病原体的演变提供独特的见解转录后水平，应广泛适用于其他密切相关但在表型上不同的物种。