Manipulating a Virulence Switch to Combat Acinetobacter baumannii Infections

操纵毒力开关来对抗鲍曼不动杆菌感染

• 批准号: 10347186
• 负责人: Philip N. Rather
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347186
• 关键词: Acinetobacter; Acinetobacter baumannii; Animal Model; Antibiotic Resistance; Antibiotics; Attenuated; Attenuated Vaccines; Automobile Driving; Back; Cells; Complex; Development; Disease; Exhibits; Family; Frequencies; Funding; Genes; Hospitals; Human; Individual; Infection; Intervention; Lighting; Lung; Lung infections; Microbial Biofilms; Military Hospitals; Military Personnel; Modeling; Multi-Drug Resistance; Mus; Pathway interactions; Phenotype; Prevention; Regulation; Regulatory Pathway; Regulon; Resistance; Role; Signal Transduction; Testing; Thick; Vaccines; Variant; Virulence; Virulent; Work; World Health Organization; attenuation; capsule; cell motility; cell type; combat; comparative; emerging pathogen; experimental study; high throughput screening; immunogenic; in vivo; inhibitor; military injury; mutant; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; quorum sensing; resistant strain; small molecule; transcriptome

Acinetobacter baumannii is a nosocomial pathogen responsible for an increasing number of infections in VA, civilian and military hospitals. This proposal will extend novel findings in our lab, where work has identified that A. baumannii cells can exist in two subpopulations, one virulent and one avirulent. These subpopulations can rapidly interconvert and we have identified a central regulator of this switch. This TetR-type regulator is encoded by the ABUW_1645 gene and overexpression of this regulator drives cells from the virulent state to the avirulent state where they are now locked. Previous work identified a complex regulatory network where a LysR-type regulator (ABUW_1132) activates ABUW_1645 expression and two additional TetR regulators, encoded by ABUW_1959 and ABUW_2818, which drives cells into the avirulent state. Individual overexpression of either ABUW_1959 or ABUW_2818 also drives virulent cells into an avirulent state, where they are now locked. The identification of this switch controlling virulence and our understanding of its regulation now paves the way for translational interventions to exploit this switch and render cells avirulent. First, we will identify genes controlled by all three regulators that contribute to the loss of virulence. The role of these genes will be tested by constructing the appropriate mutants and testing in animal models. Next, we will take advantage of the locked avirulent state to develop a live attenuated A. baumannii vaccine strain. Lastly, small molecules that drive cells from the virulent to the avirulent state will be identified by high-throughput screening. Ultimately, these inhibitors may result in the development of novel therapies to disable virulence in this increasingly important bacterial pathogen.

鲍曼不动杆菌是一种医院病原体， 退伍军人事务部、民用和军用医院的感染人数。这项建议会 扩展我们实验室的新发现，在那里工作已经确定，A。鲍氏细胞 可以存在于两个亚群中，一个是有毒的，一个是无毒的。这些 亚群可以迅速相互转换，我们已经确定了一个中央调节器， 这个开关。该TetR型调节子由ABUW_1645基因编码， 该调节因子的过度表达驱动细胞从毒性状态到无毒状态。 说明它们现在被锁定的位置。以前的工作确定了一个复杂的监管 LysR型调节器（ABUW_1132）激活ABUW_1645的网络 表达和两个另外的TetR调节子，由ABUW_1959和 ABUW_2818，其驱动细胞进入无毒状态。个人 ABUW_1959或ABUW_2818的过表达也驱动毒性细胞 变成一个无毒的状态，它们现在被锁在那里。这个的鉴定 控制毒力的开关和我们对其调节的理解， 翻译干预的方式来利用这个开关，使细胞无毒。 首先，我们将确定由所有三种调节因子控制的基因，这些基因有助于 丧失毒性。这些基因的作用将通过构建 合适的突变体和动物模型中的测试。接下来，我们将利用 以开发减毒活A.鲍曼不动杆菌疫苗 株最后，小分子驱动细胞从有毒到无毒 将通过高通量筛选来鉴定状态。最终，这些抑制剂 可能导致开发新的治疗方法来禁用这种病毒的毒力。 越来越重要的细菌病原体。