Defining a novel small RNA associated with Pseudomonas aeruginosa infection

定义与铜绿假单胞菌感染相关的新型小RNA

基本信息

批准号：
10218648
负责人：
Marvin Whiteley
金额：
$ 23.73万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-18 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218648
关键词：
Acute Address Adopted Affect Bacteria Bacterial Physiology Biochemical Biological Biology Code Cues Development Environment Foundations Future Gene Expression Gene Expression Profile Genes Genetic Goals Growth Health Human In Vitro Infection Investigation Knowledge Laboratories Laboratory culture Life Style Link Microbial Biofilms Modeling Molecular Target Mus Outcome Oxygen Pathogenesis Physiology Prevention strategy Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection RNA Research Personnel Role Shapes Signal Transduction Small RNA Taxonomy Therapeutic Intervention Transcript Work Wound models acute infection base chronic infection chronic wound comparative deprivation design differential expression experimental study fitness host colonization in vivo in vivo Model insight novel novel therapeutic intervention opportunistic pathogen pathogenic bacteria targeted treatment transcriptome transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY Understanding bacterial physiology during host infection is critical for designing effective prevention and treatment strategies. Traditionally our knowledge of bacterial pathogenesis has been derived from experiments conducted in standard laboratory models. Due to the limitations of these models in mimicking human infection and the fact that bacterial physiology is largely shaped by the environment, important features associated with bacterial pathogenesis can be overlooked in these studies. In this proposal, we aim to understand a novel gene expression signature of Pseudomonas aeruginosa (Pa) during human infection. Pa is a prominent causative agent of a wide variety of acute and chronic infections in humans. Through comparative transcriptomic analysis, we recently identified an uncharacterized gene (PA1414) that is often the most highly expressed Pa gene during human infection. However, no function has yet been attributed to this gene. Here we provide multiple lines of evidence demonstrating that: (1) PA1414 can be induced by host-associated environmental signals such as oxygen deprivation, which in turn promotes Pa biofilm formation. (2) PA1414 encodes a novel small RNA (sRNA). (3) induction of PA1414 promotes a localized non-disseminating chronic infection in a mouse wound model. Combined with the fact that PA1414 is restricted to the taxonomic group of Pa, we hypothesize that this sRNA is a key player in governing the acute-to-chronic infection switch in Pa. Our hypothesis will be addressed by experiments proposed in two specific aims. First, we will define how PA1414 induction impacts on Pa gene expression to alter its lifestyle during infection. Second, we will elucidate the mechanism of action of the PA1414- encoded sRNA and uncover its molecular targets. The information generated from this study will fill a critical void in our understanding of Pa physiology during human infection. In addition, considering that PA1414 is a well- conserved Pa-specific gene and the encoded sRNA is highly abundant in humans, this work will lay the foundation for future development of novel therapeutic strategies targeting Pa infection.

项目摘要了解宿主感染期间细菌生理学对于设计有效的预防和治疗策略。传统上，我们对细菌发病机理的了解是从实验中得出的在标准实验室模型中进行。由于这些模型在模仿人类感染中的局限性细菌生理学在很大程度上是由环境塑造的事实，与之相关的重要特征在这些研究中，细菌发病机理可以忽略。在此提案中，我们旨在了解一个新颖的基因人类感染期间铜绿假单胞菌（PA）的表达特征。 PA是一个突出的因果关系人类各种急性和慢性感染的代理。通过比较转录组分析，我们最近确定了一个未表征的基因（PA1414），通常是在人类感染。但是，尚未归因于该基因。在这里，我们提供多行证明：（1）PA1414可以由宿主相关的环境信号（例如）诱导氧气剥夺，进而促进PA生物膜的形成。（2）PA1414编码一种新型的小RNA（SRNA）。（3）PA1414的诱导促进了小鼠伤口模型中局部的非隔离性慢性感染。加上PA1414仅限于PA的分类学组的事实，我们假设这个SRNA 是管理PA中急性到智感染开关的关键参与者。我们的假设将由实验提出了两个具体目标。首先，我们将定义PA1414诱导如何影响PA基因表达在感染过程中改变其生活方式。其次，我们将阐明PA1414-的作用机理编码SRNA并发现其分子靶标。这项研究产生的信息将填补关键的空隙在我们对人类感染期间PA生理学的理解中。此外，考虑到PA1414是一个很好的保守的PA特异性基因和编码的SRNA在人类中高度丰富，这项工作将放置针对PA感染的新型治疗策略的未来发展基础。