Investigating the role of conserved signaling modules in medically important Acinetobacter species

研究保守信号模块在医学上重要的不动杆菌物种中的作用

• 批准号: 10238825
• 负责人: Ramiro Patino
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238825
• 关键词: Accounting; Acinetobacter; Acinetobacter Infections; Acute; Adenylate Cyclase; Afghanistan; Antibiotic Resistance; Antibiotics; Bacteria; Binding; Biochemical; Bioinformatics; Biological Assay; Cellular biology; Chemicals; Complex; Critical Illness; Cues; Cyclic AMP; Cyclic AMP Receptor Protein; Disease; Environment; Escherichia coli; Exhibits; Genes; Genetic Transcription; Genome; Grant; Growth; Homologous Gene; Homologous Protein; Human; Immunocompetent; Individual; Infection; Iraq; Knowledge; Life Style; Liquid substance; Locomotion; Mediating; Medical; Methods; Microscopy; Morbidity - disease rate; Multi-Drug Resistance; Nosocomial Infections; Output; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Physiology; Pilum; Pneumonia; Process; Production; Proteins; Pseudomonas aeruginosa; Public Health; Resistance; Role; Second Messenger Systems; Signal Transduction; Soft Tissue Infections; Solid; Surface; System; Technology; Testing; Type II Secretion System Pathway; Virulence; Virulence Factors; Work; bacterial genetics; base; cell motility; experimental study; healthcare-associated infections; human disease; innovation; insight; interest; mortality; mutant; novel; opportunistic pathogen; pathogen; pathogenic bacteria; prevent; programs; response; transcriptome; transcriptome sequencing; transcriptomics; wound; wounded soldier

Project summary Medically important Acinetobacter species are opportunistic bacterial pathogens that can cause devastating disease in hospitalized patients and are responsible for ~2% of nosocomial infections in the US. These species are emerging as a public health threat worldwide due to their tendency to exhibit multidrug-, or even, pandrug-resistance. Therefore, we urgently need to develop new methods to treat and prevent MDR Acinetobacter infections. Critical for this advance is a detailed understanding of how these species cause human disease; however, much remains to be learned about the pathogenesis of Acinetobacter infections. Importantly, The Engel lab and others have identified three systems in Pseudomonas aeruginosa, another important opportunistic pathogen, that coordinately activate a virulence program in response to surface contact. These systems include the type IV pilus (TFP), the Chp chemosensory system, and the cAMP/Vfr axis. Together, these modules regulate twitching motility and expression of >200 virulence genes, such as the type II secretion system. It is intriguing that P. aeruginosa repurposed and combined together three distinct modules to regulate an acute virulence program when in other bacteria the TFP and the cAMP/Vfr axis control other processes. To test whether other bacteria utilize similar components and similar circuitry, the Engel lab performed a bioinformatics analysis to determine whether these modules were conserved and present together in other bacteria. Of high interest was the finding that medically important Acinetobacter species encode homologs of all three of these modules. Given the remarkable similarity in the lifestyles of Acinetobacter species and P. aeruginosa, including their ability to survive in diverse environments as well as to cause similar diseases in humans, I hypothesize that these three systems function coordinately to regulate the ability of a pathogenic Acinetobacter species to survive in diverse environments and to cause human disease. In Aim 1, I will use a combination of bacterial genetics, biochemical, and innovative microscopy assays to establish the functional outputs of the Acinetobacter Chp system and to determine if it is interconnected to the TFP and cAMP/Vfr modules. In Aim 2, I will make use of transcriptomic technologies to identify the virulence genes regulated by the Acinetobacter Vfr transcriptional regulator and to elucidate if Vfr activation depends on the TFP and Chp system modules. Taken together, these aims will allow me to determine whether the TFP, the Chp chemosensory system, and the cAMP/Vfr modules work together to regulate virulence in Acinetobacter species. These studies may identify new targets to develop novel antibiotics, and they might also provide a better understanding of the physiology and cell biology of medically important Acinetobacter species.

项目摘要 医学上重要的杆菌种类是机会性细菌病原体，可能导致 住院患者的毁灭性疾病，在美国造成约2％的医院感染。 由于它们倾向于表现出多药或 甚至，抗药耐药性。因此，我们迫切需要开发新方法来治疗和防止MDR 动杆菌感染。这一进步至关重要的是对这些物种如何引起人类的详细理解 疾病;然而，关于动杆菌感染的发病机理还有很多待了解。重要的是， 恩格尔实验室和其他实验室在铜绿假单胞菌中确定了三个系统，这是另一个重要的 机会性病原体，该病原体协同激活了响应表面接触的毒力程序。这些 系统包括IV型菌毛（TFP），CHP化学体系统和CAMP/VFR轴。在一起，这些 模块调节了> 200个毒力基因的运动能力和表达，例如II型分泌系统。 令人着迷的是，铜绿假单胞菌重新利用并将三个不同的模块组合在一起以调节急性 毒力计划在其他细菌中，TFP和CAMP/VFR轴控制其他过程。测试是否 其他细菌利用类似的组件和类似的电路，恩格尔实验室进行了生物信息学分析 确定这些模块是否是保守的，并在其他细菌中共同存在。兴趣很高 发现医学上重要的杆菌物种编码所有这三个模块的同源物。 鉴于活杆菌和铜绿假单胞菌的生活方式具有显着的相似性，包括它们的能力 为了在各种环境中生存以及在人类中引起类似疾病，我假设这三个 系统的功能协同起来调节致病性杆菌物种在多种多样生存的能力 环境并引起人类疾病。在AIM 1中，我将结合细菌遗传学，生化， 和创新的显微镜测定法，以建立ACINETOBACTER CHP系统的功能输出和TO 确定它是否与TFP和CAMP/VFR模块互连。在AIM 2中，我将利用转录组 识别毒力基因的技术，由vfr vfr转录器调节和TO 阐明VFR激活是否取决于TFP和CHP系统模块。综上所述，这些目标将允许 我确定TFP，CHP化学体系统和CAMP/VFR模块是否合作 调节活杆菌种类的毒力。这些研究可能会确定开发新抗生素的新靶标， 他们还可以更好地了解医学上重要的生理和细胞生物学 杆菌种类。