Identification of new or unrecognized virulence genes in hypervirulent Klebsiella pneumoniae and antivirulence genes in classical K. pneumoniae.

鉴定高毒力肺炎克雷伯菌中新的或未被识别的毒力基因和经典肺炎克雷伯菌中的抗毒力基因。

• 批准号: 9894988
• 负责人: THOMAS A RUSSO
• 金额: $ 19.59万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894988
• 关键词: Abscess; Anabolism; Animals; Antimicrobial Resistance; Biological Markers; Candidate Disease Gene; Central Nervous System Infections; Cessation of life; Clinical; Communities; Complement; Data; Disease Outbreaks; Elements; Endophthalmitis; Enterobacteriaceae; Epidemiology; Exhibits; Experimental Designs; Extended-spectrum β-lactamase; Genes; Genomics; Genotype; Goals; Healthcare; Individual; Infection; Intensive Care Units; Intraperitoneal Injections; Island; Klebsiella pneumoniae; Life; Location; Measures; Mediating; Meningitis; Microbiology; Modeling; Mus; Necrotizing fasciitis; Organ; Outcome; Pathogenicity; Phenotype; Plasmids; Pneumonia; Production; Reporting; Resistance; Role; Sepsis; Sequence Analysis; Siderophores; Site; Source; Subcutaneous Injections; Superbug; Systemic infection; Testing; Therapeutic; Tissues; Validation; Virulence; Virulence Factors; Virulent; aerobactin; antimicrobial; base; candidate marker; capsule; carbapenemase; cohort; diagnostic accuracy; extensive drug resistance; genetic element; genomic data; hazard; in vivo; insight; interest; member; mortality; mucoid; mutant; novel; optimal treatments; pathogen; prevent; tool

Project Summary/Abstract: A hypervirulent Klebsiella pneumoniae (hvKp) pathotype is undergoing global dissemination. In contrast to the usual healthcare-associated epidemiology of classical K. pneumoniae (cKp) infections, hvKp causes tissue invasive infections in otherwise healthy individuals from the community. Infection often involves multiple sites that require source control (e.g. abscesses, necrotizing fasciitis) or locations that require site-specific therapy (e.g. endophthalmitis, meningitis). Initial strains of hvKp were antimicrobial susceptible, however, recently hvKp strains have been acquiring genes that encode extended-spectrum ß-lactamases and carbapenemases. The reverse direction of transfer also can occur. Recently an extensively drug-resistant (XDR) cKp strain from sequence type ST11 that had acquired part of a virulence plasmid present in hvKp was implicated as the cause of a lethal outbreak in an intensive care unit. The prospect of a hypervirulent XDR pathogen is extremely concerning. The goal of this proposal is to increase our limited understanding of the factors and generate initial insights into the mechanisms responsible for hvKp’s hypervirulent phenotype. This, in turn, will enable logical strategies to prevent or treat infections due to this true superbug. To accomplish this, we will utilize previously generated in vivo virulence data developed with accurately defined cohorts of hvKp and cKp strains. These studies identified four strain classes: 1- prototypical hvKp strains that possessed known virulence factors (VFs) and were fully virulent in vivo; 2- hvKp strains that possessed known VFs but were less virulent than prototypical hvKp strains in vivo; 3- prototypical cKp strains that did not possess known hvKp VFs and were significantly less virulent in vivo compared to prototypical hvKp strains; and 4- cKp strains that did not possess known hvKp VFs but were more virulent in vivo compared to prototypical cKp strains. These strain classes will be used as “tools” to identify candidate genes that encode VFs or anti-VFs via genomic sequencing, sequence analysis and delineation of gene sets, and subsequent appropriate comparisons (aim 1). Putative novel or unrecognized VFs and anti-VFs will be prioritized, isogenic mutant and complemented derivatives will be generated, and these constructs will be assessed in in vivo pneumonia and systemic infection models (aim 2). The deliverables of this proposal will be the identification and in vivo validation of new or unrecognized VFs and/or lack of anti-VFs that contribute to hvKp’s hypervirulent phenotype.

项目摘要/摘要： 一种高毒力肺炎克雷伯菌 (hvKp) 病型正在全球传播。相比之下 经典肺炎克雷伯菌 (cKp) 感染的常见医疗保健相关流行病学，hvKp 会导致组织 来自社区的其他健康个体的侵入性感染。感染通常涉及多个部位 需要控制源头（例如脓肿、坏死性筋膜炎）或需要针对性治疗的部位 （例如眼内炎、脑膜炎）。 hvKp 的初始菌株对抗菌药物敏感，但是最近 hvKp 菌株已获得编码广谱β-内酰胺酶和碳青霉烯酶的基因。这 也可能发生反向传输。最近，一种广泛耐药 (XDR) cKp 菌株来自 序列类型 ST11 已获得 hvKp 中存在的毒力质粒的一部分，被认为是 重症监护病房爆发致命疫情的原因。高毒力 XDR 病原体的前景极其乐观 有关。 该提案的目标是增加我们对这些因素的有限理解并产生初步见解 深入了解 hvKp 的高毒力表型的机制。反过来，这将启用逻辑策略 预防或治疗这种真正的超级细菌引起的感染。为了实现这一点，我们将利用之前生成的 使用准确定义的 hvKp 和 cKp 菌株组开发的体内毒力数据。这些研究 确定了四种菌株类别： 1- 具有已知毒力因子 (VF) 的原型 hvKp 菌株和 体内具有完全毒性； 2- hvKp 菌株具有已知的 VF，但毒性低于原型菌株 hvKp 体内菌株； 3- 原型 cKp 菌株不具有已知的 hvKp VF，并且显着 与典型的 hvKp 菌株相比，体内毒力较低；和 4- cKp 菌株，不具有已知的 hvKp 但与典型的 cKp 菌株相比，VF 在体内的毒性更强。这些菌株类别将用作 通过基因组测序、序列分析来识别编码 VF 或抗 VF 的候选基因的“工具” 基因组的描述，以及随后的适当比较（目标 1）。假定的小说或 未识别的VF和抗VF将被优先考虑，同基因突变体和互补衍生物将被优先考虑 生成，并且这些构建体将在体内肺炎和全身感染模型中进行评估（目标 2）。 该提案的成果将是新的或未识别的 VF 的识别和体内验证 和/或缺乏导致 hvKp 超毒力表型的抗 VF。