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

• 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
• 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

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 了解宿主感染期间的细菌生理学对于设计有效的预防和治疗方案至关重要。 治疗策略。传统上，我们对细菌致病机理的认识来自实验 在标准实验室模型中进行。由于这些模型在模拟人类感染方面的局限性， 以及细菌生理学在很大程度上受环境影响的事实， 在这些研究中可能忽略了细菌的发病机制。在这个提议中，我们的目标是了解一个新的基因， 铜绿假单胞菌（Pa）在人类感染期间的表达特征。Pa是一个突出的使役 是人类各种急性和慢性感染的病原体。通过比较转录组学分析， 我们最近鉴定了一个未鉴定的基因（PA 1414），它通常是在哺乳动物中表达最高的Pa基因。 人类感染然而，还没有功能被归因于该基因。在这里，我们提供了多行 有证据表明：（1）PA 1414可被宿主相关的环境信号诱导， 缺氧，这反过来又促进Pa生物膜形成。(2)PA 1414编码一种新的小RNA（sRNA）。 (3)PA 1414的诱导促进小鼠伤口模型中的局部非传播性慢性感染。 结合PA 1414仅限于Pa分类群的事实，我们假设该sRNA 是管理宾夕法尼亚州急性到慢性感染转换的关键人物。我们的假设将通过以下方式来解决： 实验提出了两个具体目标。首先，我们将确定PA 1414诱导对Pa基因的影响 在感染期间改变其生活方式。第二，我们将阐明PA 1414的作用机制， 编码sRNA并揭示其分子靶点。这项研究产生的信息将填补一个关键的空白 我们对人类感染过程中Pa生理学的理解。此外，考虑到PA 1414是良好的- 保守的Pa特异性基因和编码的sRNA在人类中高度丰富，这项工作将奠定 为将来开发靶向Pa感染的新型治疗策略奠定基础。