Virulence-Associated Accessory Genomic Elements of Pseudomonas aeruginosa

铜绿假单胞菌毒力相关的辅助基因组元件

• 批准号: 8595780
• 负责人: Jonathan P Allen
• 金额: $ 4.92万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595780
• 关键词: Accounting; Address; Antibiotic Resistance; Antibiotics; Bacteremia; Bioinformatics; Biological Markers; Blood Circulation; Clinical; Collection; Complex; Development; Elements; Foundations; Future; Genes; Genome; Genomics; Goals; Human; Indium; Individual; Infection; Infectious Diseases Research; Intervention; Lead; Modeling; Morbidity - disease rate; Mus; Names; Nosocomial Infections; Pathogenesis; Pathogenicity; Patients; Phenotype; Play; Positioning Attribute; Pseudomonas aeruginosa; Research; Resistance; Role; Testing; Therapeutic; Therapeutic Intervention; Toxin; Virulence; Virulence Factors; Virulent; Work; attenuation; cell killing; comparative genomics; experience; genome sequencing; innovation; macrophage; member; microbial; mortality; mouse model; next generation; novel; novel therapeutics; pathogen; public health relevance; research study; respiratory

DESCRIPTION (provided by applicant): Identification of novel virulence determinants is a crucial goal of infectious disease research and necessary for a comprehensive understanding of the complex mechanisms that encompass microbial pathogenicity. This research is critical for the development of innovative treatment options in the era of increasing antibiotic resistance. Pseudomonas aeruginosa is a significant opportunistic pathogen and the cause of various nosocomial infections. Despite what is understood about P. aeruginosa pathogenesis, individual strains can substantially differ in their virulence and responsiveness to current treatment options. The specific factors responsible for much of this difference in virulence are currently unknown. A large portion of the P. aeruginosa genome varies between individual strains, and this variable "accessory genome" has been shown to play a role in the pathogenesis of P. aeruginosa. It is hypothesized that novel virulence factors within the P. aeruginosa accessory genome account for some of the significant differences in virulence between strains. The hypothesis will be tested by completing the following two specific aims: In Aim 1, the genome sequences of approximately 100 P. aeruginosa clinical bloodstream isolates will be determined utilizing next generation Illumina sequencing. A directed bioinformatic approach will be used to determine regions of the P. aeruginosa accessory genome that are significantly associated with highly virulent isolates, thus likely to harbor novel virulence factors. In Aim 2, piecemeal deletin of virulence-associated accessory genomic elements will be performed to identify the specific gene(s) responsible for virulence in a mouse bacteremia model. Upon completion of these specific aims, it is expected that an extensive set of novel virulence factors will be identified tat directly contribute to the pathogenesis of highly virulent P. aeruginosa strains. The information gained from the proposed experiments will lead to elucidation of the complex pathogenic mechanisms of P. aeruginosa. Additionally these factors could be used as specific biomarkers of highly virulent strains allowing clinicians to identify patients in need of particularly aggressve interventions. Moreover, this work will lay the foundation for future studies into the development of innovative therapeutic interventions.

描述（由申请人提供）：新型毒力决定因素的识别是传染病研究的关键目标，对于涵盖涵盖微生物致病性的复杂机制的全面理解所必需。这项研究对于在增加抗生素耐药性时代的创新治疗方案的发展至关重要。铜绿假单胞菌是一种重要的机会性病原体，也是各种医院感染的原因。尽管对铜绿假单胞菌发病机理有所了解，但单个菌株的毒力和对当前治疗选择的反应性可能会大不相同。目前尚不清楚导致这种毒力差异的大部分差异的特定因素。铜绿假单胞菌基因组的很大一部分在单个菌株之间有所不同，并且该变量“附属基因组”已显示在铜绿假单胞菌的发病机理中起作用。假设铜绿假单胞菌附件基因组中的新型毒力因子涉及菌株之间毒力的某些显着差异。该假设将通过完成以下两个特定目的来检验：在AIM 1中，将使用下一代Illumina测序确定大约100p。Aeruginosa临床血流分离株的基因组序列。一种定向的生物信息学方法将用于确定与高毒性分离株显着相关的铜绿假单胞菌附件基因组的区域，因此可能具有新颖的毒力因子。在AIM 2中，将执行与毒力相关的辅助基因组元素的零碎缺失，以识别小鼠菌血症模型中负责毒力的特定基因。完成这些特定目标后，预计将发现一组新的毒力因子直接促成高毒性铜绿假单胞菌菌株的发病机理。从提出的实验中获得的信息将导致铜绿假单胞菌的复杂致病机制阐明。此外，这些因素可以用作高毒性菌株的特定生物标志物，使临床医生能够识别需要特别侵略干预措施的患者。此外，这项工作将为未来研究创新治疗干预措施的发展奠定基础。